Prodrugs of fused-bicyclic C5aR antagonists

ABSTRACT

The present disclosure provides, inter alia, Compounds of Formulae IA, IB, IC, IIA, IIB and IIC or pharmaceutically acceptable salts thereof that are modulators of the C5a receptor. Also provided are pharmaceutical compositions and methods of use including the treatment of diseases or disorders involving pathologic activation from C5a and non-pharmaceutical applications.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application claims the benefit of priority under 35 U.S.C. § 119(e)to U.S. Provisional Application Ser. No. 62/651,512 filed Apr. 2, 2018,the disclosure of which is incorporated herein by reference in itsentirety.

STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSOREDRESEARCH AND DEVELOPMENT

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REFERENCE TO A “SEQUENCE LISTING,” A TABLE, OR A COMPUTER PROGRAMLISTING APPENDIX SUBMITTED ON A COMPACT DISK

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BACKGROUND OF THE INVENTION

The complement system plays a central role in the clearance of immunecomplexes and in immune responses to infectious agents, foreignantigens, virus infected cells and tumor cells. Inappropriate orexcessive activation of the complement system can lead to harmful, andeven potentially life-threatening consequences due to severeinflammation and resulting tissue destruction. These consequences areclinically manifested in various disorders including septic shock;myocardial, as well as, intestinal ischemia/reperfusion injury; graftrejection; organ failure; nephritis; pathological inflammation; andautoimmune diseases.

The complement system is composed of a group of proteins that arenormally present in the serum in an inactive state. Activation of thecomplement system encompasses mainly three distinct pathways, i.e., theclassical, the alternative, and the lectin pathway (V. M. Holers, InClinical Immunology: Principles and Practice, ed. R. R. Rich, MosbyPress; 1996, 363-391): 1) The classical pathway is acalcium/magnesium-dependent cascade, which is normally activated by theformation of antigen-antibody complexes. It can also be activated in anantibody-independent manner by the binding of C-reactive protein,complexed with ligand, and by many pathogens including gram-negativebacteria. 2) The alternative pathway is a magnesium-dependent cascadewhich is activated by deposition and activation of C3 on certainsusceptible surfaces (e.g. cell wall polysaccharides of yeast andbacteria, and certain biopolymer materials). 3) The lectin pathwayinvolves the initial binding of mannose-binding lectin and thesubsequent activation of C2 and C4, which are common to the classicalpathway (Matsushita, M. et al., J. Exp. Med. 176: 1497-1502 (1992);Suankratay, C. et al., J. Immunol. 160: 3006-3013 (1998)).

The activation of the complement pathway generates biologically activefragments of complement proteins, e.g. C3a, C4a and C5a anaphylatoxinsand C5b-9 membrane attack complexes (MAC), all which mediateinflammatory responses by affecting leukocyte chemotaxis; activatingmacrophages, neutrophils, platelets, mast cells and endothelial cells;and increasing vascular permeability, cytolysis and tissue injury.

Complement C5a is one of the most potent proinflammatory mediators ofthe complement system. (The anaphylactic C5a peptide is 100 times morepotent, on a molar basis, in eliciting inflammatory responses than C3a.)C5a is the activated form of C5 (190 kD, molecular weight). C5a ispresent in human serum at approximately 80 μg/ml (Kohler, P. F. et al,J. Immunol. 99: 1211-1216 (1967)). It is composed of two polypeptidechains, α and β, with approximate molecular weights of 115 kD and 75 kD,respectively (Tack, B. F. et al., Biochemistry 18: 1490-1497 (1979)).Biosynthesized as a single-chain promolecule, C5 is enzymaticallycleaved into a two-chain structure during processing and secretion.After cleavage, the two chains are held together by at least onedisulphide bond as well as noncovalent interactions (Ooi, Y. M. et al,J. Immunol. 124: 2494-2498(1980)).

C5 is cleaved into the C5a and C5b fragments during activation of thecomplement pathways. The convertase enzymes responsible for C5activation are multi-subunit complexes of C4b, C2a, and C3b for theclassical pathway and of (C3b)₂, Bb, and P for the alternative pathway(Goldlust, M. B. et al., J. Immunol. 113: 998-1007 (1974); Schreiber, R.D. et al, Proc. Natl. Acad. Sci. 75: 3948-3952 (1978)). C5 is activatedby cleavage at position 74-75 (Arg-Leu) in the α-chain. Afteractivation, the 11.2 kD, 74 amino acid peptide C5a from theamino-terminus portion of the α-chain is released. Both C5a and C3a arepotent stimulators of neutrophils and monocytes (Schindler, R. et al.,Blood 76: 1631-1638 (1990); Haeffner-Cavaillon, N. et al., J. Immunol.138: 794-700 (1987); Cavaillon, J. M. et al., Eur. J. Immunol. 20:253-257 (1990)).

In addition to its anaphylatoxic properties, C5a induces chemotacticmigration of neutrophils (Ward, P. A. et al., J. Immunol. 102: 93-99(1969)), eosinophils (Kay, A. B. et al., Immunol. 24: 969-976 (1973)),basophils (Lett-Brown, M. A. et al., J. Immunol. 117: 246-252 1976)),and monocytes (Snyderman, R. et al., Proc. Soc. Exp. Biol. Med. 138:387-390 1971)). Both C5a and C5b-9 activate endothelial cells to expressadhesion molecules essential for sequestration of activated leukocytes,which mediate tissue inflammation and injury (Foreman, K. E. et al., J.Clin. Invest. 94: 1147-1155 (1994); Foreman, K. E. et al., Inflammation20: 1-9 (1996); Rollins, S. A. et al., Transplantation 69: 1959-1967(2000)). C5a also mediates inflammatory reactions by causing smoothmuscle contraction, increasing vascular permeability, inducing basophiland mast cell degranulation and inducing release of lysosomal proteasesand oxidative free radicals (Gerard, C. et al., Ann. Rev. Immunol. 12:775-808 (1994)). Furthermore, C5a modulates the hepatic acute-phase geneexpression and augments the overall immune response by increasing theproduction of TNF-α, IL-1-β, IL-6, IL-8, prostaglandins and leukotrienes(Lambris, J. D. et al., In: The Human Complement System in Health andDisease, Volanakis, J. E. ed., Marcel Dekker, New York, pp. 83-118).

The anaphylactic and chemotactic effects of C5a are believed to bemediated through its interaction with the C5a receptor. The human C5areceptor (C5aR) is a 52 kD membrane bound G protein-coupled receptor,and is expressed on neutrophils, monocytes, basophils, eosinophils,hepatocytes, lung smooth muscle and endothelial cells, and renalglomerular tissues (Van-Epps, D. E. et al., J. Immunol. 132: 2862-2867(1984); Haviland, D. L. et al., J. Immunol. 154:1861-1869 (1995);Wetsel, R. A., Immunol. Leff. 44: 183-187 (1995); Buchner, R. R. et al,Immunol. 155: 308-315 (1995); Chenoweth, D. E. et al, Proc. Natl. Acad.Sci. 75: 3943-3947 (1978); Zwirner, J. et al., Mol. Immunol. 36:877-884(1999)). The ligand-binding site of C5aR is complex and consists of atleast two physically separable binding domains. One binds the C5a aminoterminus (amino acids 1-20) and disulfide-linked core (amino acids21-61), while the second binds the C5a carboxy-terminal end (amino acids62-74) (Wetsel, R. A., Curr. Opin. Immunol. 7: 48-53 (1995)).

C5a plays important roles in inflammation and tissue injury. Incardiopulmonary bypass and hemodialysis, C5a is formed as a result ofactivation of the alternative complement pathway when human blood makescontact with the artificial surface of the heart-lung machine or kidneydialysis machine (Howard, R. J. et al., Arch. Surg. 123: 1496-1501(1988); Kirklin, J. K. et al., J. Cardiovasc. Surg. 86: 845-857 (1983);Craddock, P. R. et at, N. Engl. J. Med. 296: 769-774 (1977)). C5a causesincreased capillary permeability and edema, bronchoconstriction,pulmonary vasoconstriction, leukocyte and platelet activation andinfiltration to tissues, in particular the lung (Czermak, B. J. et al.,J. Leukoc. Biol. 64: 40-48 (1998)). Administration of an anti-C5amonoclonal antibody was shown to reduce cardiopulmonary bypass andcardioplegia-induced coronary endothelial dysfunction (Tofukuji, M. etal., J. Thorac. Cardiovasc. Surg. 116: 1060-1068 (1998)).

C5a is also involved in acute respiratory distress syndrome (ARDS),Chronic Obstructive Pulmonary Disorder (COPD) and multiple organ failure(MOF) (Hack, C. E. et al., Am. J. Med. 1989: 86: 20-26; Hammerschmidt DE et at Lancet 1980; 1: 947-949; Heideman M. et al. J. Trauma 1984; 4:1038-1043; Marc, M M, et al., Am. J. Respir. Cell and Mol. Biol., 2004:31: 216-219). C5a augments monocyte production of two importantpro-inflammatory cytokines, TNF-α and IL-1. C5a has also been shown toplay an important role in the development of tissue injury, andparticularly pulmonary injury, in animal models of septic shock(Smedegard Get al. Am. J. Pathol. 1989; 135: 489-497; Markus, S., et at,FASEB Journal (2001), 15: 568-570). In sepsis models using rats, pigsand non-human primates, anti-05a antibodies administered to the animalsbefore treatment with endotoxin or E. coli resulted in decreased tissueinjury, as well as decreased production of IL-6 (Smedegard, G. et al.,Am. J. Pathol. 135: 489-497 (1989); Hopken, U. et at, Eur. J. Immunol.26: 1103-1109 (1996); Stevens, J. H. et at, J Clin. Invest. 77:1812-1816 (1986)). More importantly, blockade or C5a with anti-05apolyclonal antibodies has been shown to significantly improve survivalrates in a caecal ligation/puncture model of sepsis in rats (Czermak, B.J. et al., Nat. Med. 5: 788-792 (1999)). This model share many aspectsof the clinical manifestation of sepsis in humans. (Parker, S. J. etal., Br. J. Surg. 88: 22-30 (2001)). In the same sepsis model, anti-05aantibodies were shown to inhibit apoptosis of thymocytes (Guo, R. F. etal., J. Clin. Invest. 106: 1271-1280 (2000)) and prevent MOF(Huber-Lang, M. et al., J. Immunol. 166: 1193-1199 (2001)). Anti-C5aantibodies were also protective in a cobra venom factor model of lunginjury in rats, and in immune complex-induced lung injury (Mulligan, M.S. et al. J. Clin. Invest. 98: 503-512 (1996)). The importance of C5a inimmune complex-mediated lung injury was later confirmed in mice (Bozic,C. R. et al., Science 26: 1103-1109 (1996)).

C5a is found to be a major mediator in myocardial ischemia-reperfusioninjury. Complement depletion reduced myocardial infarct size in mice(Weisman, H. F. et al., Science 249: 146-151 (1990)), and treatment withanti-05a antibodies reduced injury in a rat model of hindlimbischemia-reperfusion (Bless, N. M. et al., Am. J. Physiol. 276: L57-L63(1999)). Reperfusion injury during myocardial infarction was alsomarkedly reduced in pigs that were retreated with a monoclonal anti-05aIgG (Amsterdam, E. A. et al., Am. J. Physiol. 268:H448-H457 (1995)). Arecombinant human C5aR antagonist reduces infarct size in a porcinemodel of surgical revascularization (Riley, R. D. et al., J. Thorac.Cardiovasc. Surg. 120: 350-358 (2000)).

C5a driven neutrophils also contribute to many bullous diseases (e.g.,bullous pemphigoid, pemphigus vulgaris and pemphigus foliaceus). Theseare chronic and recurring inflammatory disorders clinicallycharacterized by sterile blisters that appear in the sub-epidermal spaceof the skin and mucosa. While autoantibodies to keratinocytes located atthe cutaneous basement membranes are believed to underlie the detachmentof epidermal basal keratinocytes from the underlying basement membrane,blisters are also characterized by accumulation of neutrophils in boththe upper dermal layers and within the blister cavities. In experimentalmodels a reduction of neutrophils or absence of complement (total orC5-selective) can inhibit formation of sub-epidermal blisters, even inthe presence of high auto-antibody titers.

Complement levels are elevated in patients with rheumatoid arthritis(Jose, P. J. et al., Ann. Rheum. Dis. 49: 747-752 (1990); Grant, E. P.,et al., J. of Exp. Med., 196(11): 1461-1471, (2002)), lupus nephritis(Bao, L., et al., Eur. J. of Immunol, 35(8), 2496-2506, (2005)) andsystemic lupus erythematosus (SLE) (Porcel, J. M. et al., Clin. Immunol.Immunopathol. 74: 283-288 (1995)). C5a levels correlate with theseverity of the disease state. Collagen-induced arthritis in mice andrats resembles the rheumatoid arthritic disease in human. Mice deficientin the C5a receptor demonstrated a complete protection from arthritisinduced by injection of monoclonal anti-collagen Abs (Banda, N. K., etal., J. of Immunol., 2003, 171: 2109-2115). Therefore, inhibition of C5aand/or C5a receptor (C5aR) could be useful in treating these chronicdiseases.

The complement system is believed to be activated in patients withinflammatory bowel disease (IBD) and is thought to play a role in thedisease pathogenesis. Activated complement products were found at theluminal face of surface epithelial cells, as well as in the muscularismucosa and submucosal blood vessels in IBD patients (Woodruff, T. M., etal., J of Immunol., 2003, 171: 5514-5520).

C5aR expression is upregulated on reactive astrocytes, microglia, andendothelial cells in an inflamed human central nervous system (Gasque,P. et al., Am. J. Pathol. 150: 31-41 (1997)). C5a might be involved inneurodegenerative diseases, such as Alzheimer disease (Mukherjee, P. etal., J. Neuroimmunol. 105: 124-130 (2000); O'Barr, S. et al., J.Neuroimmunol. (2000) 105: 87-94; Farkas, I., et al. J. Immunol. (2003)170:5764-5771), Parkinson's disease, Pick disease and transmissiblespongiform encephalopathies. Activation of neuronal C5aR may induceapoptosis (Farkas I et al. J. Physiol. 1998; 507: 679-687). Therefore,inhibition of C5a and/or C5aR could also be useful in treatingneurodegenerative diseases.

There is some evidence that C5a production worsens inflammationassociated with atopic dermatitis (Neuber, K., et al., Immunology73:83-87, (1991)), and chronic urticaria (Kaplan, A. P., J. AllergyClin. Immunol. 114; 465-474, (2004).

Psoriasis is now known to be a T cell-mediated disease (Gottlieb, E. L.et al., Nat. Med. 1: 442-447 (1995)). However, neutrophils and mastcells may also be involved in the pathogenesis of the disease (Terui, T.et al., Exp. Dermatol. 9: 1-10; 2000); Werfel, T. et al., Arch.Dermatol. Res. 289: 83-86 (1997)). Neutrophil accumulation under thestratum corneum is observed in the highly inflamed areas of psoriaticplaques, and psoriatic lesion (scale) extracts contain highly elevatedlevels of C5a and exhibit potent chemotactic activity towardsneutrophils, an effect that can be inhibited by addition of a C5aantibody. T cells and neutrophils are chemo-attracted by C5a (Nataf, S.et al., J. Immunol. 162: 4018-4023 (1999); Tsuji, R. F. et al, J.Immunol. 165: 1588-1598 (2000); Cavaillon, J. M. et al, Eur. J. Immunol.20: 253-257 (1990)). Additionally expression of C5aR has beendemonstrated in plasmacytoid dendritic cells (pDC) isolated from lesionsof cutaneous lupus erythematous and these cells were shown to displaychemotactic behavior towards C5a, suggesting that blockade of C5aR onpDC might be efficacious in reducing pDC infiltration into inflamed skinin both SLE and psoriasis. Therefore C5a could be an importanttherapeutic target for treatment of psoriasis.

Immunoglobulin G-containing immune complexes (IC) contribute to thepathophysiology in a number of autoimmune diseases, such as systemiclupus erthyematosus, rheumatoid arthritis, Sjogren's disease,Goodpasture's syndrome, and hypersensitivity pneumonitis (Madaio, M. P.,Semin. Nephrol. 19: 48-56 (1999); Korganow, A. S. et al., Immunity 10:451-459 (1999); Bolten, W. K., Kidney Int. 50: 1754-1760 (1996); Ando,M. et al., Curr. Opin. Pulm. Med. 3: 391-399 (1997)). These diseases arehighly heterogeneous and generally affect one or more of the followingorgans: skin, blood vessels, joints, kidneys, heart, lungs, nervoussystem and liver (including cirrhosis and liver fibrosis). The classicalanimal model for the inflammatory response in these IC diseases is theArthus reaction, which features the infiltration of polymorphonuclearcells, hemorrhage, and plasma exudation (Arthus, M., C. R. Soc. Biol.55: 817-824 (1903)). Recent studies show that C5aR deficient mice areprotected from tissue injury induced by IC (Kohl, J. et al., MotImmunol. 36: 893-903 (1999); Baumann, U. et al., J. Immunol. 164:1065-1070 (2000)). The results are consistent with the observation thata small peptidic anti-05aR antagonist inhibits the inflammatory responsecaused by IC deposition (Strachan, A. J. et al., J. Immunol. 164:6560-6565 (2000)). Together with its receptor, C5a plays an importantrole in the pathogenesis of IC diseases. Inhibitors of C5a and C5aRcould be useful to treat these diseases.

Descripton of Related Art:

Non-peptide based C5a receptor antagonist have been reported as beingeffective for treating endotoxic shock in rats (Stracham, A. J., et al.,J. of Immunol. (2000), 164(12): 6560-6565); and for treating IBD in arat model (Woodruff, T. M., et al., J. of Immunol., 2003, 171:5514-5520). Non-peptide based C5a receptor modulators also have beendescribed in the patent literature by Neurogen Corporation, (e.g.,WO2004/043925, WO2004/018460, WO2005/007087, WO03/082826, WO03/08828,WO02/49993, WO03/084524); Dompe S.P.A. (WO02/029187); The University ofQueenland (WO2004/100975); and ChemoCentryx (WO2010/075257).

There is considerable experimental evidence in the literature thatimplicates increased levels of C5a with a number of diseases anddisorders, in particular in autoimmune and inflammatory diseases anddisorders. Thus, there remains a need in the art for new small organicmolecule modulators, e.g., agonists, preferably antagonists, partialagonists, of the C5a receptor (C5aR) that are useful for inhibitingpathogenic events, e.g., chemotaxis, associated with increased levelsanaphylatoxin activity. The present invention fulfills this and otherneeds.

BRIEF SUMMARY OF THE INVENTION

In one aspect, the present invention provide compounds of Formulae (IA),(IB), (IC), (IIA), (IIB), and (IIC):

or a pharmaceutically acceptable salt thereof, wherein the symbols,letters and subscripts n, m, a, b, e, X¹, R¹, R^(2a), R^(2b), R³, R⁴,R⁵, R⁶, R⁷ and R⁸ have the meanings provided in the description below.

In addition to the compounds provided herein, the present inventionfurther provides pharmaceutical compositions containing one or more ofthese compounds, as well as methods for the use of these compounds intherapeutic methods, primarily to treat diseases associated C5asignaling activity.

In yet another aspect, the present invention provides methods ofdiagnosing disease in an individual. In these methods, the compoundsprovided herein are administered in labeled form to a subject, followedby diagnostic imaging to determine the presence or absence of C5aRand/or the localization of cells expressing a C5aR receptor. In arelated aspect, a method of diagnosing disease is carried out bycontacting a tissue or blood sample with a labeled compound as providedherein and determining the presence, absence, amount, or localization ofC5aR in the sample.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows release of active compound intermediate 4 from the compoundof Example 1 (0.5 mg/kg mole equiv., AUC=4,160 ng.hr/mL).

FIG. 2 shows release of active compound intermediate 1 from the compoundof Example 4 (0.5 mg/kg mole equiv., AUC=753 ng.hr/mL)

DETAILED DESCRIPTION OF THE INVENTION Abbreviation and Definitions

The term “alkyl”, by itself or as part of another substituent, means,unless otherwise stated, a straight or branched chain hydrocarbonradical, having the number of carbon atoms designated (i.e. C₁₋₈ meansone to eight carbons). Examples of alkyl groups include methyl, ethyl,n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl,n-hexyl, n-heptyl, n-octyl, and the like. The term “alkenyl” refers toan unsaturated alkyl group having one or more double bonds. Similarly,the term “alkynyl” refers to an unsaturated alkyl group having one ormore triple bonds. Examples of such unsaturated alkyl groups includevinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), isobutenyl,2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl,3-butynyl, and the higher homologs and isomers. The term “cycloalkyl”refers to hydrocarbon rings having the indicated number of ring atoms(e.g., C₃₋₆ cycloalkyl) and being fully saturated or having no more thanone double bond between ring vertices. “Cycloalkyl” is also meant torefer to bicyclic and polycyclic hydrocarbon rings such as, for example,bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, etc. The term“heterocycloalkyl” refers to a cycloalkyl group that contain from one tofive heteroatoms selected from N, O, and S, wherein the nitrogen andsulfur atoms are optionally oxidized, and the nitrogen atom(s) areoptionally quaternized. The heterocycloalkyl may be a monocyclic, abicyclic or a polycylic ring system. Non limiting examples ofheterocycloalkyl groups include pyrrolidine, imidazolidine,pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin,dioxolane, phthalimide, piperidine, 1,4-dioxane, morpholine,thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide,piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone,tetrahydrofuran, tetrhydrothiophene, quinuclidine, and the like. Aheterocycloalkyl group can be attached to the remainder of the moleculethrough a ring carbon or a heteroatom.

The term “alkylene” by itself or as part of another substituent means adivalent radical derived from an alkane, as exemplified by—CH₂CH₂CH₂CH₂—. Typically, an alkyl (or alkylene) group will have from 1to 24 carbon atoms, with those groups having 10 or fewer carbon atomsbeing preferred in the present invention. A “lower alkyl” or “loweralkylene” is a shorter chain alkyl or alkylene group, generally havingfour or fewer carbon atoms. Similarly, “alkenylene” and “alkynylene”refer to the unsaturated forms of “alkylene” having double or triplebonds, respectively.

The term “heteroalkyl,” by itself or in combination with another term,means, unless otherwise stated, a stable straight or branched chain, orcyclic hydrocarbon radical, or combinations thereof, consisting of thestated number of carbon atoms and from one to three heteroatoms selectedfrom the group consisting of O, N, Si and S, and wherein the nitrogenand sulfur atoms may optionally be oxidized and the nitrogen heteroatommay optionally be quaternized. The heteroatom(s) O, N and S may beplaced at any interior position of the heteroalkyl group. The heteroatomSi may be placed at any position of the heteroalkyl group, including theposition at which the alkyl group is attached to the remainder of themolecule. Examples include —CH₂—CH₂—O—CH₃, —CH₂—CH₂—NH—CH₃,—CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃, —CH₂—CH₂, —S(O)—CH₃,—CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃, —Si(CH₃)₃, —CH₂—CH═N—OCH₃, and—CH═CH—N(CH₃)—CH₃. Up to two heteroatoms may be consecutive, such as,for example, —CH₂—NH—OCH₃ and —CH₂—O—Si(CH₃)₃. Similarly, the terms“heteroalkenyl” and “heteroalkynyl” by itself or in combination withanother term, means, unless otherwise stated, an alkenyl group oralkynyl group, respectively, that contains the stated number of carbonsand having from one to three heteroatoms selected from the groupconsisting of O, N, Si and S, and wherein the nitrogen and sulfur atomsmay optionally be oxidized and the nitrogen heteroatom may optionally bequaternized. The heteroatom(s) O, N and S may be placed at any interiorposition of the heteroalkyl group.

The term “heteroalkylene” by itself or as part of another substituentmeans a divalent radical, saturated or unsaturated or polyunsaturated,derived from heteroalkyl, as exemplified by —CH₂—CH₂—S—CH₂CH₂— and—CH₂—S—CH₂—CH₂—NH—CH₂—, —O—CH₂—CH═CH—, —CH₂—CH═C(H)CH₂—O—CH₂— and—S—CH₂—C≡C—. For heteroalkylene groups, heteroatoms can also occupyeither or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy,alkyleneamino, alkylenediamino, and the like).

The terms “alkoxy,” “alkylamino” and “alkylthio” (or thioalkoxy) areused in their conventional sense, and refer to those alkyl groupsattached to the remainder of the molecule via an oxygen atom, an aminogroup, or a sulfur atom, respectively. Additionally, for dialkylaminogroups, the alkyl portions can be the same or different and can also becombined to form a 3-7 membered ring with the nitrogen atom to whicheach is attached. Accordingly, a group represented as —NR^(a)R^(b) ismeant to include piperidinyl, pyrrolidinyl, morpholinyl, azetidinyl andthe like.

The term “hydroxyalkyl” is used in its conventional sense, and refers tobranched or straight chain alkyl group substituted with at least onehydroxyl group. The hydroxyl group may be at any position in the alkylgroup. For example, the term “C₁₋₄ hydroxylalkyl” is meant to includehydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl, and thelike.

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. Additionally, terms such as “haloalkyl,” aremeant to include monohaloalkyl and polyhaloalkyl. For example, the term“C₁₋₄haloalkyl” is mean to include trifluoromethyl,2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

The term “aryl” means, unless otherwise stated, a polyunsaturated,typically aromatic, hydrocarbon group which can be a single ring ormultiple rings (up to three rings) which are fused together or linkedcovalently. The term “heteroaryl” refers to aryl groups (or rings) thatcontain from one to five heteroatoms selected from N, O, and S, whereinthe nitrogen and sulfur atoms are optionally oxidized, and the nitrogenatom(s) are optionally quaternized. A heteroaryl group can be attachedto the remainder of the molecule through a heteroatom. Non-limitingexamples of aryl groups include phenyl, naphthyl and biphenyl, whilenon-limiting examples of heteroaryl groups include pyridyl, pyridazinyl,pyrazinyl, pyrimindinyl, triazinyl, quinolinyl, quinoxalinyl,quinazolinyl, cinnolinyl, phthalaziniyl, benzotriazinyl, purinyl,benzimidazolyl, benzopyrazolyl, benzooxazolyl, benzotriazolyl,benzisoxazolyl, isobenzofuryl, isoindolyl, indolizinyl, benzotriazinyl,thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, pyrrolopyridyl,imidazopyridines, benzothiaxolyl, benzofuranyl, benzothienyl, indolyl,quinolyl, isoquinolyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl,imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl,pyrrolyl, thiazolyl, furyl, thienyl and the like. Substituents for eachof the above noted aryl and heteroaryl ring systems are selected fromthe group of acceptable substituents described below.

The term “pharmaceutically acceptable salts” is meant to include saltsof the active compounds which are prepared with relatively nontoxicacids or bases, depending on the particular substituents found on thecompounds described herein. When compounds of the present inventioncontain relatively acidic functionalities, base addition salts can beobtained by contacting the neutral form of such compounds with asufficient amount of the desired base, either neat or in a suitableinert solvent. Examples of salts derived frompharmaceutically-acceptable inorganic bases include aluminum, ammonium,calcium, copper, ferric, ferrous, lithium, magnesium, manganic,manganous, potassium, sodium, zinc and the like. Salts derived frompharmaceutically-acceptable organic bases include salts of primary,secondary and tertiary amines, including substituted amines, cyclicamines, naturally-occurring amines and the like, such as arginine,betaine, caffeine, choline, N,N′-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperadine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine and the like. When compounds of the presentinvention contain relatively basic functionalities, acid addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired acid, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable acid additionsalts include those derived from inorganic acids like hydrochloric,hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived from relatively nontoxic organic acids likeacetic, propionic, isobutyric, malonic, benzoic, succinic, suberic,fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric,tartaric, methanesulfonic, and the like. Also included are salts ofamino acids such as arginate and the like, and salts of organic acidslike glucuronic or galactunoric acids and the like (see, for example,Berge, S. M., et al, “Pharmaceutical Salts”, Journal of PharmaceuticalScience, 1977, 66, 1-19). Certain specific compounds of the presentinvention contain both basic and acidic functionalities that allow thecompounds to be converted into either base or acid addition salts.

The neutral forms of the compounds may be regenerated by contacting thesalt with a base or acid and isolating the parent compound in theconventional manner. The parent form of the compound differs from thevarious salt forms in certain physical properties, such as solubility inpolar solvents, but otherwise the salts are equivalent to the parentform of the compound for the purposes of the present invention.

In addition to salt forms, the present invention provides compoundswhich are in a prodrug form. Prodrugs of the compounds described hereinare those compounds that readily undergo chemical changes underphysiological conditions to provide the compounds of the presentinvention. Additionally, prodrugs can be converted to the compounds ofthe present invention by chemical or biochemical methods in an ex vivoenvironment. For example, prodrugs can be slowly converted to thecompounds of the present invention when placed in a transdermal patchreservoir with a suitable enzyme or chemical reagent.

Certain compounds of the present invention can exist in unsolvated formsas well as solvated forms, including hydrated forms. In general, thesolvated forms are equivalent to unsolvated forms and are intended to beencompassed within the scope of the present invention. Certain compoundsof the present invention may exist in multiple crystalline or amorphousforms. In general, all physical forms are equivalent for the usescontemplated by the present invention and are intended to be within thescope of the present invention.

Certain compounds of the present invention possess asymmetric carbonatoms (optical centers) or double bonds; the racemates, diastereomers,geometric isomers, regioisomers and individual isomers (e.g., separateenantiomers) are all intended to be encompassed within the scope of thepresent invention. The compounds of the present invention may alsocontain unnatural proportions of atomic isotopes at one or more of theatoms that constitute such compounds. For example, the compounds may beradiolabeled with radioactive isotopes, such as for example tritium(³H), iodine-125 (¹²⁵I) or carbon-14 (¹⁴C). All isotopic variations ofthe compounds of the present invention, whether radioactive or not, areintended to be encompassed within the scope of the present invention.

The term “prodrug component” refers to a group that provides desiredproperties to a compound which improve, for example, the compound'sstability, circulation time in vivo, or solubility. A compound bearing aprodrug component is metabolized (generally via hydrolysis orenzymatically) following administration to a subject—resulting in anactive compound.

Compounds with a prodrug component may only become active upon cleavage,but compounds with a prodrug component may have activity in theirunreacted forms. Additionally, a prodrug component itself may be active.Examples of prodrug components contemplated in this disclosure include,but are not limited to, phosphate, phosphomethyl, hydroxymethyl, aminoacid, dipeptide and tripeptide moieties. Further embodimentscontemplated are further described herein.

The term “amino acid” refers to naturally occurring and non-naturalamino acids. Non-natural amino acids refer to compounds that have thesame basic chemical structure as a naturally occurring amino acid, i.e.,an a carbon that is bound to a hydrogen, a carboxyl group, an aminogroup, and an R group, such as, but not limited to, homoserine,norleucine, methionine sulfoxide, methionine methyl sulfonium. Suchanalogs have modified R groups (such as, 2,5-diaminopentanoic acid) ormodified peptide backbones, but retain the same basic chemical structureas a naturally occurring amino acid. The amino acids of the presentdisclosure include N-methylated and N-acylated moieties. When theterminal group of the amino acid is an N atom, it may be di-methylated.

As used herein, a wavy line, that intersects a single, double or triplebond in any chemical structure depicted herein, represent the pointattachment of the single, double, or triple bond to the remainder of themolecule.

Description of the Embodiments

Compounds

In one aspect, the present invention provides compounds of Formulae(IA), (IB), (IC), (IIA), (IIB), and (IIC):

or a pharmaceutically acceptable salt thereof, wherein,ring vertex a is N or C(R^(2c)), ring vertex b is N or C(R^(2d)), andring vertex e is N or C(R^(2e)), wherein no more than one of a, b and eis N;X¹ is selected from the group consisting of a bond, C₁₋₈ alkylene, C(O),C(O)—C₁₋₄ alkylene, and S(O)₂;R¹ is selected from the group consisting of

-   -   a) 5- to 10-membered heteroaryl having from 1 to 4 heteroatoms        as ring vertices selected from N, O and S;    -   b) C₆₋₁₀ aryl;    -   c) C₃₋₈ cycloalkyl;    -   d) 4- to 8-membered heterocycloalkyl having from 1 to 2        heteroatoms as ring vertices selected from N, O and S; and    -   e) C₁₋₈ alkyl, C₁₋₈ alkoxy, C₁₋₈haloalkyl, —C(O)NR^(1a)R^(1b),        and —CO₂R^(1a); wherein R^(1a) and R^(1b) are each independently        selected from the group consisting of hydrogen, C₁₋₈ alkyl,        C₆₋₁₀ aryl, and —C₁₋₆ alkylene-C₆₋₁₀ aryl;        wherein the group —X¹—R¹ is optionally substituted with 1 to 5        R^(x) substituents;        R^(2a) and R^(2c) are each independently selected from the group        consisting of hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, —S—C₁₋₆ alkyl,        —C₁₋₆ alkyl-O—C₁₋₆ alkyl, —C₁₋₆alkyl-S—C₁₋₆ alkyl, CN, and        halogen, and at least one of R^(2a) and R^(2e) is other than        hydrogen;        R^(2b), R^(2c), and R^(2d) are each independently selected from        the group consisting of hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆        haloalkyl, haloalkyl, —S—C₁₋₆ alkyl, —C₁₋₆ alkyl-O—C₁₋₆ alkyl,        —C₁₋₆ alkyl-S—C₁₋₆ alkyl, cyano, and halogen;        each R³ is independently selected from the group consisting of        hydroxyl, C₁₋₄ alkyl, C₁₋₄ haloalkyl and C₁₋₄ hydroxyalkyl, and        optionally two R³ groups on the same carbon atom are combined to        form oxo (═O), and optionally two R³ groups and the carbon atoms        they are attached to form a 3-6 membered ring with 0-2        hetereoatoms as ring members selected from O, N, and S;        R⁴ is a member selected from the group consisting of: —NHP¹,        —NHC(O)NHP¹, —CH₂NHP¹ and —CH₂NHC(O)NHP¹;        each R⁵ is independently selected from the group consisting of        C₁₋₈ alkyl, C₁₋₈ alkoxy, C₁₋₈ haloalkyl, C₁₋₈ haloalkoxy, C₁₋₈        hydroxyalkyl, halogen, OH, CN, C(O)R^(5a) and CO₂R^(5a);        R^(5′) is a member selected from the group consisting of        hydrogen, C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₁₋₈ hydroxyalkyl,        C(O)R^(5a) and CO₂R^(5a); wherein each R^(5a) is independently        selected from the group consisting of hydrogen, C₁₋₄ alkyl, and        C₁₋₄ haloalkyl;        R⁶ is a member selected from the group consisting of hydrogen,        C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, —S—C₁₋₆ alkyl, —C₁₋₆        alkyl-O—C₁₋₆ alkyl, —C₁₋₆ alkyl-S—C₁₋₆ alkyl, cyano, and        halogen;        R⁷ is P¹; and        R⁸ is —CH₂OP¹;        each P¹ is a prodrug component;        each R^(x) is independently selected from the group consisting        of halogen, CN, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄        haloalkoxy, C₁₋₄ hydroxyalkyl, C₂₋₄ alkenyl, C₃₋₆ cycloalkyl,        CO₂—C₁₋₄ alkyl, and CONH₂;        the subscript m is 0, 1, 2, 3 or 4; and        the subscript n is 0, 1, 2 or 3.

In one group of embodiments, the compounds provided herein have Formula(IA). In another group of embodiments, the compounds provided hereinhave Formula (IB). In still another group of embodiments, the compoundsprovided herein have Formula (IC). In yet another group of embodiments,the compounds provided herein have Formula (IIA). In another group ofembodiments, the compounds provided herein have Formula (IIB). In stillanother group of embodiments, the compounds provided herein have Formula(IIC).

In some embodiments for the compounds of formula (IA), (IB), (IC),(IIA), (IIB), (IIC), or a pharmaceutically acceptable salt thereof, aswell as any of the groups of embodiments noted above, P¹ is selectedfrom the group consisting of:

-   -   wherein each R⁹ is independently selected from the group        consisting of H and C₁₋₃ alkyl; and        each R¹⁰ is independently selected from the group consisting of        H, C₁₋₃ alkyl, phenyl, and benzyl.

In some embodiments for the compounds of formula (IA), (IB), (IC),(IIA), (IIB), (IIC), or a pharmaceutically acceptable salt thereof, aswell as any of the groups of embodiments noted above, P¹ is selectedfrom the group consisting of:

wherein

-   -   each R^(y) is independently selected from the group consisting        of        -   —OP(O)(OB^(y1))₂, —OC(O)CH₂N(R^(y2))₂, —N(R^(y2))₂, and            piperazine;    -   each R^(y1) is independently selected form the group consisting        of H, C₁₋₃ alkyl, and benzyl;    -   each R^(y2) is independently H or C₁₋₃ alkyl; and    -   each phenyl ring bearing an R^(y) or —CH₂R^(y) substituent is        further substituted with from 0 to 3 members independently        selected from the group consisting of nitro, halogen, CN, CF₃,        C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, and        C₁₋₄ hydroxyalkyl.

In some embodiments for the compounds of formula (IA), (IB), (IC),(IIA), (IIB), (IIC), or a pharmaceutically acceptable salt thereof, aswell as any of the groups of embodiments noted above, P¹ is selectedfrom the group consisting of —CH₂OH, —P(O)(OR¹⁰)₂, and —CH₂—O—P(O)(OR¹⁰)₂, wherein each R¹⁰ is independently selected from the groupconsisting of H, C₁₋₃ alkyl, phenyl, and benzyl,

In some embodiments for the compounds of formula (IA), (IB), (IC),(IIA), (IIB), (IIC), or a pharmaceutically acceptable salt thereof, aswell as any of the groups of embodiments noted above, P¹ is selectedfrom the group consisting of an amino acid, a dipeptide, and atripeptide. In some embodiments, the amino acid, dipeptide, ortripeptide are natural amino acids. In some embodiments the amino acid,dipeptide, or tripeptide moieties are independently selected from thegroup consisting of glycine, alanine, valine, leucine, isoleucine,lysine, cysteine, aspartate, glutamate, histidine, and phenylalanine,wherein the N atom of each amino acid unit may be methylated oracylated.

The amino acids of the present disclosure can be covalently linked tothe remainder of the molecule via any suitable means. Suitable linkagesinclude, but are not limited to, amide formation between an amine groupa hydroxyl group, ester formation between a carboxylic acid group and ahydroxyl group, and sulfonamide formation (N—S linkage) between a thiogroup and an amino group. Typically, amino acids are covalently linkedto the remainder of the molecule via the alpha amino group or the alphacarboxylic acid; however, when the R group of the amino acid includes afunctional group, this may also serve as the linkage point. For example,the carboxylic acid of a glutamate may service as the linkage point tothe remainder of the molecule. Similarly, the thiol of a cysteine mayalso serve as the linkage point to the remainder of the molecule.

In some embodiments for the compounds of formula (IA), (IB), (IC),(IIA), (IIB), (IIC), or a pharmaceutically acceptable salt thereof, aswell as any of the groups of embodiments noted above, P¹ is selectedfrom the group consisting of:

With reference to the compounds of formula (IA), (IB), (IC), (IIA),(IIB), (IIC), or a pharmaceutically acceptable salt thereof, as well asany of the groups of embodiments noted above, in certain selectedembodiments, X¹ is a bond; in other selected embodiments, X¹ is C(O); instill other selected embodiments, X¹ is C₁₋₈ alkylene; in yet otherselected embodiments, X¹ is C(O)—C₁₋₄ alkylene or S(O)₂.

With reference to the compounds of formula (IA), (IB), (IC), (IIA),(IIB), (IIC), or a pharmaceutically acceptable salt thereof, as well asany of the groups or selected embodiments noted above, in some furtherembodiments, wherein R¹ is a 5- to 10-membered heteroaryl having from 1to 4 heteroatoms as ring vertices selected from N, O and S; and whereinthe group —X¹—R¹ is optionally substituted with 1 to 4 R^(x)substituents. In still further embodiments, R¹ is selected from thegroup consisting of pyrazolyl, pyridyl, pyrimidinyl, imidazolyl,thiazolyl, thiadiazolyl and pyrazinyl; and wherein the group —X¹—R¹ isoptionally substituted with 1 to 4 IV substituents.

With reference to the compounds of formula (IA), (IB), (IC), (IIA),(IIB), (IIC), or a pharmaceutically acceptable salt thereof, as well asany of the groups or selected embodiments noted above, in some furtherembodiments, wherein R¹ is C₆₋₁₀ aryl; and wherein the group —X¹—R¹ isoptionally substituted with 1 to 4 IV substituents. In still furtherembodiments, R¹ is phenyl; and wherein the group —X¹—R¹ is optionallysubstituted with 1 to 4 R^(x) substituents.

With reference to the compounds of formula (IA), (IB), (IC), (IIA),(IIB), (IIC), or a pharmaceutically acceptable salt thereof, as well asany of the groups or selected embodiments noted above, in some furtherembodiments, R¹ is C₃₋₈ cycloalkyl; and wherein the group —X¹—R¹ isoptionally substituted with 1 to 4 R^(x) substituents. In still furtherembodiments, R¹ is selected from the group consisting of cyclobutyl,cyclopentyl and cyclohexyl; and wherein the group —X¹—R¹ is optionallysubstituted with 1 to 4 R^(x) substituents.

With reference to the compounds of formula (IA), (IB), (IC), (IIA),(IIB), (IIC), or a pharmaceutically acceptable salt thereof, as well asany of the groups or selected embodiments noted above, in some furtherembodiments, R¹ is a 4- to 8-membered heterocycloalkyl having from 1 to2 heteroatoms as ring vertices selected from N, O and S; and wherein thegroup —X¹—R¹ is optionally substituted with 1 to 4 R^(x) substituents.In still further selected embodiments, R¹ is selected from the groupconsisting of oxetanyl, tetrahydrofuranyl, tetrahydropyranyl andmorpholinyl; and wherein the group —X¹—R¹ is optionally substituted with1 to 4 R^(x) substituents.

With reference to the compounds of formula (IA), (IB), (IC), (IIA),(IIB), (IIC), or a pharmaceutically acceptable salt thereof, as well asany of the groups or selected embodiments noted above, in some furtherembodiments, R¹ is selected from the group consisting of C₁₋₈ alkyl,C₁₋₈ alkoxy, C₁₋₈ haloalkyl, —C(O)NR^(1a)R^(1b), and —CO₂R^(1a); whereinR^(1a) and R^(1b) are each independently selected from the groupconsisting of hydrogen, C₁₋₈ alkyl, C₆₋₁₀ aryl, and —C₁₋₆ alkylene-C₆₋₁₀aryl; and wherein the group —X¹—R¹ is optionally substituted with 1 to 4R^(x) substituents.

With reference to the compounds of formula (IA), (IB), (IC), (IIA),(IIB), (IIC), or a pharmaceutically acceptable salt thereof, as well asany of the groups or selected embodiments noted above, in some furtherembodiments, R¹ is selected from the group consisting of phenyl,pyridyl, pyrimidinyl, and pyrazinyl; and wherein the group —X¹—R¹ isoptionally substituted with 1 to 4 R^(x) substituents.

With reference to the compounds of formula (IA), (IB), (IC), (IIA),(IIB), (IIC), or a pharmaceutically acceptable salt thereof, as well asany of the embodiments noted above, in some further embodiments, ringvertices a and b are CH; R^(2b) is H; ring vertex e is C(R^(2e)), andR^(2a) and R^(2c) are independently selected from the group consistingof C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, —O—C₁₋₆ haloalkyl, —S—C₁₋₆alkyl, —C₁₋₆ alkyl-O—C₁₋₆ alkyl, —C₁₋₆ alkyl-S—C₁₋₆ alkyl, CN, andhalogen.

With reference to the compounds of formula (IA), (IB), (IC), (IIA),(IIB), (IIC), or a pharmaceutically acceptable salt thereof, as well asany of the embodiments noted above, in some further embodiments, ringvertices a and b are CH; R^(2b) is H; ring vertex e is C(R^(2e)), andR^(2a) and R^(2e) are independently selected from the group consistingof C₁₋₆ alkyl, C₁₋₆ alkoxy and halogen.

With reference to the compounds of formula (IA), (IB), (IC), (IIA),(IIB), (IIC), or a pharmaceutically acceptable salt thereof, as well asany of the embodiments noted above, in some further embodiments, thesubscript n is 0, 1 or 2 and each R⁵, when present, is selected from thegroup consisting of F, Cl, CN, C₁₋₄ alkyl and C₁₋₄ alkoxy. In stillfurther selected embodiments, the subscript n is 0, 1 or 2 and each R⁵,when present, is selected from the group consisting of F, Cl, CN, CH₃and OCH₃.

With reference to the compounds of formula (IA), (IB), (IC), (IIA),(IIB), (IIC), or a pharmaceutically acceptable salt thereof, as well asany of the embodiments noted above, in some further embodiments, thesubscript m is 0, 1 or 2 and each R³, when present, is C₁₋₄ alkyl.

In a particular group of embodiments of the compounds of formula (IA),(IB), (IC), (IIA), (IIB), (IIC), or a pharmaceutically acceptable saltthereof, R¹ is selected from the group consisting of phenyl or pyridyl,wherein the group —X¹—R¹ is optionally substituted with 1 to 4 R^(x)substituents; ring vertices a and b are CH; R^(2b) is H; ring vertex eis C(R^(2e)), and R^(2a) and R^(2e) are independently selected from thegroup consisting of C₁₋₆ alkyl, C₁₋₆ alkoxy and halogen; m is 0, 1 or 2and each R³, when present, is CH₃, n is 0, 1 or 2 and each R⁵, whenpresent, is selected from the group consisting of F, Cl, CN, CH₃ andOCH₃.

In some embodiments of the compounds of formula (IA), (IB), (IC), (IIA),(IIB), (IIC), or a pharmaceutically acceptable salt thereof, R¹ isselected from the group consisting of

In some embodiments of the compounds of formula (IA), (IB), (IC), (IIA),(IIB), (IIC), or a pharmaceutically acceptable salt thereof, —X¹—R¹ isselected from the group consisting of:

In some embodiments of the compounds of formula (IA), (IB), (IC), (IIA),(IIB), (IIC), or a pharmaceutically acceptable salt thereof, R¹ isselected from the group consisting of:

In some embodiments of the compounds of formula (IA), (IB), (IC), (IIA),(IIB), (IIC), or a pharmaceutically acceptable salt thereof, R¹ isselected from the group consisting of:

In some embodiments of the compounds of formula (IA), (IB), (IC), (IIA),(IIB), (IIC), or a pharmaceutically acceptable salt thereof, R¹ isselected from the group consisting of:

With reference to the compounds of formula (IA), (IB), (IC), (IIA),(IIB), (IIC), or a pharmaceutically acceptable salt thereof, as well asany of the embodiments noted above, in

some further embodiments, the group is selected from the groupconsisting of

With reference to the compounds of formula (IA), (IB), (IC), (IIA),(IIB), (IIC), or a pharmaceutically acceptable salt thereof, as well asany of the embodiments noted above, in some further embodiments, whereinn is 0.

With reference to the compounds of formula (IA), (IB), (IC), (IIA),(IIB), (IIC), or a pharmaceutically acceptable salt thereof, as well asany of the embodiments noted above, in some further embodiments, thesubscript n is 2 and the two R³ groups are on the same carbon atom andare combined to form oxo (═O).

In some embodiments, the compound of the present disclosure is acompound described in the Examples section and the accompanying Tables.

Preparation of Compounds

Certain compounds of the invention can be prepared following methodologyas described in the Examples section of this document. In addition, thesyntheses of certain intermediate compounds that are useful in thepreparation of compounds of the invention are also described.

Pharmaceutical Compositions

In addition to the compounds provided above, compositions for modulatingC5a activity in humans and animals will typically contain apharmaceutical carrier or diluent.

The term “composition” as used herein is intended to encompass a productcomprising the specified ingredients in the specified amounts, as wellas any product which results, directly or indirectly, from combinationof the specified ingredients in the specified amounts. By“pharmaceutically acceptable” it is meant the carrier, diluent orexcipient must be compatible with the other ingredients of theformulation and not deleterious to the recipient thereof.

The pharmaceutical compositions for the administration of the compoundsof this invention may conveniently be presented in unit dosage form andmay be prepared by any of the methods well known in the art of pharmacyand drug delivery. All methods include the step of bringing the activeingredient into association with the carrier which constitutes one ormore accessory ingredients. In general, the pharmaceutical compositionsare prepared by uniformly and intimately bringing the active ingredientinto association with a liquid carrier or a finely divided solid carrieror both, and then, if necessary, shaping the product into the desiredformulation. In the pharmaceutical composition the active objectcompound is included in an amount sufficient to produce the desiredeffect upon the process or condition of diseases.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions and self emulsifications as described in U.S. PatentApplication 2002-0012680, hard or soft capsules, syrups, elixirs,solutions, buccal patch, oral gel, chewing gum, chewable tablets,effervescent powder and effervescent tablets. Compositions intended fororal use may be prepared according to any method known to the art forthe manufacture of pharmaceutical compositions and such compositions maycontain one or more agents selected from the group consisting ofsweetening agents, flavoring agents, coloring agents, antioxidants andpreserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets contain the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipients whichare suitable for the manufacture of tablets. These excipients may be forexample, inert diluents, such as cellulose, silicon dioxide, aluminumoxide, calcium carbonate, sodium carbonate, glucose, mannitol, sorbitol,lactose, calcium phosphate or sodium phosphate; granulating anddisintegrating agents, for example, corn starch, or alginic acid;binding agents, for example PVP, cellulose, PEG, starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated,enterically or otherwise, by known techniques to delay disintegrationand absorption in the gastrointestinal tract and thereby provide asustained action over a longer period. For example, a time delaymaterial such as glyceryl monostearate or glyceryl distearate may beemployed. They may also be coated by the techniques described in theU.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotictherapeutic tablets for control release.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin, or olive oil.Additionally, emulsions can be prepared with a non-water miscibleingredient such as oils and stabilized with surfactants such asmono-diglycerides, PEG esters and the like.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxy-ethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl, p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents. Oral solutions can be prepared in combination with, for example,cyclodextrin, PEG and surfactants.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, for example as a solution in 1,3-butane diol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The compounds of the present invention may also be administered in theform of suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials include cocoa butter andpolyethylene glycols. Additionally, the compounds can be administeredvia ocular delivery by means of solutions or ointments. Still further,transdermal delivery of the subject compounds can be accomplished bymeans of iontophoretic patches and the like. For topical use, creams,ointments, jellies, solutions or suspensions, etc., containing thecompounds of the present invention are employed. As used herein, topicalapplication is also meant to include the use of mouth washes andgargles.

The compounds of this invention may also be coupled a carrier that is asuitable polymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxy-propyl-methacrylamide-phenol,polyhydroxyethyl-aspartamide-phenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of theinvention may be coupled to a carrier that is a class of biodegradablepolymers useful in achieving controlled release of a drug, for examplepolylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcross linked or amphipathic block copolymers of hydrogels. Polymers andsemipermeable polymer matrices may be formed into shaped articles, suchas valves, stents, tubing, prostheses and the like. In one embodiment ofthe invention, the compound of the invention is coupled to a polymer orsemipermeable polymer matrix that is formed as a stent or stert-graftdevice.

The pharmaceutical compositions of the present disclosure may beformulated with one or more additional therapeutic agents. The one ormore additional therapeutic agent is selected from the group consistingof corticosteroids, steroids, immunosuppressants, Immunoglobulin Gagonists, Dipeptidyl peptidase IV inhibitors, Lymphocyte functionantigen-3 receptor antagonists, Interleukin-2 ligands, Interleukin-1beta ligand inhibitors, IL-2 receptor alpha subunit inhibitors, HGF genestimulators, IL-6 antagonists, IL-5 antagonists, Alpha 1 antitrypsinstimulators, Cannabinoid receptor antagonists, Histone deacetylaseinhibitors, AKT protein kinase inhibitors, CD20 inhibitors, Abl tyrosinekinase inhibitors, JAK tyrosine kinase inhibitors, TNF alpha ligandinhibitors, Hemoglobin modulators, TNF antagonists, proteasomeinhibitors, CD3 modulators, Hsp 70 family inhibitors, Immunoglobulinagonists, CD30 antagonists, tubulin antagonists, Sphingosine-1-phosphatereceptor-1 agonists, connective tissue growth factor ligand inhibitors,caspase inhibitors, adrenocorticotrophic hormone ligands, Btk tyrosinekinase inhibitors, Complement C1s subcomponent inhibitors,Erythropoietin receptor agonists, B-lymphocyte stimulator ligandinhibitors, Cyclin-dependent kinase-2 inhibitors, P-selectinglycoprotein ligand-1 stimulators, mTOR inhibitors, Elongation factor 2inhibitors, Cell adhesion molecule inhibitors, Factor XIII agonists,Calcineurin inhibitors, Immunoglobulin G1 agonists, Inosinemonophosphate dehydrogenase inhibitors, Complement C1s subcomponentinhibitors, Thymidine kinase modulators, Cytotoxic T-lymphocyteprotein-4 modulators, Angiotensin II receptor antagonists, AngiotensinII receptor modulators, TNF superfamily receptor 12A antagonists, CD52antagonists, Adenosine deaminase inhibitors, T-cell differentiationantigen CD6 inhibitors, FGF-7 ligands, dihydroorotate dehydrogenaseinhibitors, Syk tyrosine kinase inhibitors, Interferon type I receptorantagonists, Interferon alpha ligand inhibitors, Macrophage migrationinhibitory factor inhibitors, Integrin alpha-V/beta-6 antagonists,Cysteine protease stimulators, p38 MAP kinase inhibitors, TP53 geneinhibitors, Shiga like toxin I inhibitors, Fucosyltransferase 6stimulators, Interleukin 22 ligands, IRS1 gene inhibitors, Proteinkinase C stimulators, Protein kinase C alpha inhibitors, CD74antagonists, Immunoglobulin gamma Fc receptor IIB antagonists, T-cellantigen CD7 inhibitors, CD95 antagonists, N acetylmannosamine kinasestimulators, Cardiotrophin-1 ligands, Leukocyte elastase inhibitors,CD40 ligand receptor antagonists, CD40 ligand modulators, IL-17antagonists, TLR-2 antagonists, Mannan-binding lectin serine protease-2(MASP-2) inhibitors, Factor B inhibitors, Factor D inhibitors, C3 aRmodulators, C5aR2 modulators, T cell receptor antagonists, PD-1inhibitors, PD-L1 inhibitors, TIGIT inhibitors, TIM-3 inhibitors, LAG-3inhibitors, VISTA inhibitors, STING agonists, IDO inhibitors, adenosinereceptor modulators, CD39 inhibitors, CD73 inhibitors, antagonists ofthe chemokine receptors, especially CXCR1, CXCR2, CXCR3, CXCR4, CXCR7,CCR1, CCR2, CCR3, CCR4, CCR5, CCR7, CCR7, CCR9, CX3CR1 and CXCR6, andcombinations thereof.

In some embodiments, the one or more additional therapeutic agent isselected from the group consisting of obinutuzumab, rituximab,ocrelizumab, cyclophosphamide, prednisone, hydrocortisone,hydrocortisone acetate, cortisone acetate, tixocortol pivalate,prednisolone, methylprednisolone, triamcinolone acetonide, triamcinolonealcohol, mometasone, amcinonide, budesonide, desonide, fluocinonide,fluocinolone acetonide, halcinonide, betamethasone, betamethasone sodiumphosphate, dexamethasone, dexamethasone sodium phosphate, fluocortolone,hydrocortisone-17-valerate, halometasone, alclometasone dipropionate,beclomethasone, betamethasone valerate, betamethasone dipropionate,prednicarbate, clobetasone-17-butyrate, clobetasol-17-propionate,fluocortolone caproate, fluocortolone pivalate, fluprednidene acetate,hydrocortisone-17-butyrate, hydrocortisone-17-aceponate,hydrocortisone-17-buteprate, ciclesonide and prednicarbate, GB-0998,immuglo, begelomab, alefacept, aldesleukin, gevokizumab, daclizumab,basiliximab, inolimomab, beperminogene perplasmid, sirukumab,tocilizumab, clazakizumab, mepolizumab, fingolimod, panobinostat,triciribine, nilotinib, imatinib, tofacitinib, momelotinib, peficitinib,itacitinib, infliximab, PEG-bHb-CO, etanercept, ixazomib, bortezomib,muromonab, otelixizumab, gusperimus, brentuximab vedotin, Ponesimod,KRP-203, FG-3019, emricasan, corticotropin, ibrutinib, cinryze,conestat, methoxy polyethylene glycol-epoetin beta, belimumab,blisibimod, atacicept, seliciclib, neihulizumab, everolimus, sirolimus,denileukin diftitox, LMB-2, natalizumab, catridecacog, ciclosporin,tacrolimus, voclosporin, voclosporin, canakinumab, mycophenolate,mizoribine, CE-1145, TK-DLI, abatacept, belatacept, olmesartanmedoxomil, sparsentan, TXA-127, BIIB-023, alemtuzumab, pentostatin,itolizumab, palifermin, leflunomide, PRO-140, cenicriviroc,fostamatinib, anifrolumab, sifalimumab, BAX-069, BG-00011, losmapimod,QPI-1002, ShigamAbs, TZ-101, F-652, reparixin, ladarixin, PTX-9908,aganirsen, APH-703, sotrastaurin, sotrastaurin, milatuzumab, SM-101,T-Guard, APG-101, DEX-M74, cardiotrophin-1, tiprelestat, ASKP-1240,BMS-986004, HPH-116, KD-025, OPN-305, TOL-101, defibrotide,pomalidomide, Thymoglobulin, laquinimod, remestemcel-L, Equineantithymocyte immunoglobulin, Stempeucel, LIV-Gamma, Octagam 10%,t2c-001, 99mTc-sestamibi, Clairyg, Prosorba, pomalidomide, laquinimod,teplizumab, FCRx, solnatide, foralumab, ATIR-101, BPX-501, ACP-01,ALLO-ASC-DFU, irbesartan+propagermanium, ApoCell, cannabidiol, RGI-2001,saratin, anti-CD3 bivalent antibody-diphtheria toxin conjugate, NOX-100,LT-1951, OMS721, ALN-CC5, ACH-4471, AMY-101, Acthar gel, and CD4+CD25+regulatory T-cells, MEDI7814, P32, P59, pembrolizumab, nivolumab,atezolizumab, avelumab, durvalumab, CCX354, CCX721, CCX9588, CCX140,CCX872, CCX598, CCX6239, CCX587, CCX624, CCX282, CCX025, CCX507, CCX430,CCX765, CCX758, CCX771, CCX662, CCX650, and combinations thereof.Further discussions of combination therapy are included in the “Methodsof Use” section of this application.

Methods of Use

The compounds of the invention may be used as agonists, (preferably)antagonists, partial agonists, inverse agonists, of C5a receptors in avariety of contexts, both in vitro and in vivo. In one embodiment, thecompounds of the invention are C5aR antagonist that can be used toinhibit the binding of C5a receptor ligand (e.g., C5a) to C5a receptorin vitro or in vivo. In general, such methods comprise the step ofcontacting a C5a receptor with a sufficient amount of one or more C5areceptor modulators as provided herein, in the presence of C5a receptorligand in aqueous solution and under conditions otherwise suitable forbinding of the ligand to C5a receptor. The C5a receptor may be presentin suspension (e.g., in an isolated membrane or cell preparation), in acultured or isolated cell, or in a tissue or organ.

Preferably, the amount of C5a receptor modulator contacted with thereceptor should be sufficient to inhibit C5a binding to C5a receptor invitro as measured, for example, using a radioligand binding assay,calcium mobilization assay, or chemotaxis assay as described herein.

In one embodiment of the invention, the C5a modulators of the inventionare used to modulate, preferably inhibit, the signal-transducingactivity of a C5a receptor, for example, by contacting one or morecompound(s) of the invention with a C5a receptor (either in vitro or invivo) under conditions suitable for binding of the modulator(s) to thereceptor. The receptor may be present in solution or suspension, in acultured or isolated cell preparation or within a patient. Anymodulation of the signal transducing activity may be assessed bydetecting an effect on calcium ion calcium mobilization or by detectingan effect on C5a receptor-mediated cellular chemotaxis. In general, aneffective amount of C5a modulator(s) is an amount sufficient to modulateC5a receptor signal transducing activity in vitro within a calciummobilization assay or C5a receptor-mediated cellular chemotaxis within amigration assay.

When compounds of the invention are used to inhibit C5areceptor-mediated cellular chemotaxis, preferably leukocyte (e.g.,neutrophil) chemotaxis, in an in vitro chemotaxis assay, such methodscomprise contacting white blood cells (particularly primate white bloodcells, especially human white blood cells) with one or more compounds ofthe invention. Preferably the concentration is sufficient to inhibitchemotaxis of white blood cells in an in vitro chemotaxis assay, so thatthe levels of chemotaxis observed in a control assay are significantlyhigher, as described above, than the levels observed in an assay towhich a compound of the invention has been added.

In another embodiment, the compounds of the present invention furthercan be used for treating patients suffering from conditions that areresponsive to C5a receptor modulation. As used herein, the term“treating” or “treatment” encompasses both disease-modifying treatmentand symptomatic treatment, either of which may be prophylactic (i.e.,before the onset of symptoms, in order to prevent, delay or reduce theseverity of symptoms) or therapeutic (i.e., after the onset of symptoms,in order to reduce the severity and/or duration of symptoms). As usedherein, a condition is considered “responsive to C5a receptormodulation” if modulation of C5a receptor activity results in thereduction of inappropriate activity of a C5a receptor. As used herein,the term “patients” include primates (especially humans), domesticatedcompanion animals (such as dogs, cats, horses, and the like) andlivestock (such as cattle, pigs, sheep, and the like), with dosages asdescribed herein.

Conditions that can be Treated by C5a Modulation:

Autoimmune disorders—e.g., Rheumatoid arthritis, systemic lupuserythematosus, Guillain-Barre syndrome, pancreatitis, lupus nephritis,lupus glomerulonephritis, psoriasis, Crohn's disease, vasculitis,irritable bowel syndrome, dermatomyositis, multiple sclerosis, bronchialasthma, dense deposit disease, pemphigus, pemphigoid, scleroderma,myasthenia gravis, autoimmune hemolytic and thrombocytopenic states,Goodpasture's syndrome (and associated glomerulonephritis and pulmonaryhemorrhage), C3-glomerulopathy, C3-glomerulonephritis,membranoproliferative glomerulonephritis, Kawasaki disease, IGsnephropathy, immunovasculitis, tissue graft rejection, graft versus hostdisease, hyperacute rejection of transplanted organs; and the like.

Inflammatory disorders and related conditions—e.g., Neutropenia, sepsis,septic shock, Alzheimer's disease, multiple sclerosis, neutrophilia,stroke, inflammatory bowel disease (IBD), inflammation associated withsevere burns, lung injury, and ischemia-reperfusion injury,osteoarthritis, as well as acute (adult) respiratory distress syndrome(ARDS), chronic pulmonary obstructive disorder (COPD), systemicinflammatory response syndrome (SIRS), atopic dermatitis, psoriasis,chronic urticaria and multiple organ dysfunction syndrome (MODS)Hemolytic uremic syndrome, atypical hemolytic uremic syndrome (aHUS).Also included are pathologic sequellae associated with insulin-dependentdiabetes mellitus (including diabetic retinopathy), lupus nephropathy,Heyman nephritis, membranous nephritis and other forms ofglomerulonephritis, contact sensitivity responses, and inflammationresulting from contact of blood with artificial surfaces that can causecomplement activation, as occurs, for example, during extracorporealcirculation of blood (e.g., during hemodialysis or via a heart-lungmachine, for example, in association with vascular surgery such ascoronary artery bypass grafting or heart valve replacement), or inassociation with contact with other artificial vessel or containersurfaces (e.g., ventricular assist devices, artificial heart machines,transfusion tubing, blood storage bags, plasmapheresis,plateletpheresis, and the like). Also included are diseases related toischemia/reperfusion injury, such as those resulting from transplants,including solid organ transplant, and syndromes such as ischemicreperfusion injury, ischemic colitis and cardiac ischemia. Compounds ofthe instant invention may also be useful in the treatment of age-relatedmacular degeneration (Hageman et al, P.N.A.S. 102: 7227-7232, 2005).

Cardiovascular and Cerebrovascular Disorders—e.g., myocardialinfarction, coronary thrombosis, vascular occlusion, post-surgicalvascular reocclusion, atherosclerosis, traumatic central nervous systeminjury, and ischemic heart disease. In one embodiment, an effectiveamount of a compound of the invention may be administered to a patientat risk for myocardial infarction or thrombosis (i.e., a patient who hasone or more recognized risk factor for myocardial infarction orthrombosis, such as, but not limited to, obesity, smoking, high bloodpressure, hypercholesterolemia, previous or genetic history ofmyocardial infarction or thrombosis) in order reduce the risk ofmyocardial infarction or thrombosis.

Oncologic Diseases or Disorders—e.g., melanoma, lung cancer, lymphoma,sarcoma, carcinoma, fibrosarcoma, liposarcoma, chondrosarcoma,osteogenic sarcoma, angiosarcoma, lymphangiosarcoma, synovioma,mesothelioma, meningioma, leukemia, lymphoma, leiomyosarcoma,rhabdomyosarcoma, squamous cell carcinoma, basal cell carcinoma,adenocarcinoma, papillary carcinoma, cystadenocarcinoma, bronchogeniccarcinoma, renal cell carcinoma, hepatocellular carcinoma, transitionalcell carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, wilm'stumor, pleomorphic adenoma, liver cell papilloma, renal tubular adenoma,cystadenoma, papilloma, adenoma, leiomyoma, rhabdomyoma, hemangioma,lymphangioma, osteoma, chondroma, lipoma and fibroma.

Diseases of Vasculitis—Vasculitic diseases are characterized byinflammation of the vessels. Infiltration of leukocytes leads todestruction of the vessel walls, and the complement pathway is believedto play a major role in initiating leukocyte migration as well as theresultant damage manifested at the site of inflammation (Vasculitis,Second Edition, Edited by Ball and Bridges, Oxford University Press, pp47-53, 2008). The compounds provided in the present invention can beused to treat leukoclastic vasculitis, Anti-neutrophil cytoplasmicantibody (ANCA) associated vasculitis, immune vasculitis Wegener'sgranulomatosis, microscopic polyangiitis, Churg-Strauss syndrome,Henoch-Schonlein purpura, polyateritis nodosa, Rapidly ProgressiveGlomerulonephritis (RPGN), cryoglobulinaemia, giant cell arteritis(GCA), Behcet's disease and Takayasu's arteritis (TAK).

HIV infection and AIDS—C5a receptor modulators provided herein may beused to inhibit HIV infection, delay AIDS progression or decrease theseverity of symptoms or HIV infection and AIDS.

Neurodegenerative disorders and related diseases—Within further aspects,C5a antagonists provided herein may be used to treat Alzheimer'sdisease, multiple sclerosis, and cognitive function decline associatedwith cardiopulmonary bypass surgery and related procedures.

In one embodiment of the invention, the compounds of the invention canbe used for the treatment of diseases selected from the group consistingof sepsis (and associated disorders), COPD, rheumatoid arthritis, lupusnephritis and multiple sclerosis.

Treatment methods provided herein include, in general, administration toa patient an effective amount of one or more compounds provided herein.Suitable patients include those patients suffering from or susceptibleto (i.e., prophylactic treatment) a disorder or disease identifiedherein. Typical patients for treatment as described herein includemammals, particularly primates, especially humans. Other suitablepatients include domesticated companion animals such as a dog, cat,horse, and the like, or a livestock animal such as cattle, pig, sheepand the like.

In general, treatment methods provided herein comprise administering toa patient an effective amount of a compound one or more compoundsprovided herein. In a preferred embodiment, the compound(s) of theinvention are preferably administered to a patient (e.g., a human)orally or topically. The effective amount may be an amount sufficient tomodulate C5a receptor activity and/or an amount sufficient to reduce oralleviate the symptoms presented by the patient. Preferably, the amountadministered is sufficient to yield a plasma concentration of thecompound (or its active metabolite, if the compound is a pro-drug) highenough to detectably inhibit white blood cell (e.g., neutrophil)chemotaxis in vitro. Treatment regimens may vary depending on thecompound used and the particular condition to be treated; for treatmentof most disorders, a frequency of administration of 4 times daily orless is preferred. In general, a dosage regimen of 2 times daily is morepreferred, with once a day dosing particularly preferred. It will beunderstood, however, that the specific dose level and treatment regimenfor any particular patient will depend upon a variety of factorsincluding the activity of the specific compound employed, the age, bodyweight, general health, sex, diet, time of administration, route ofadministration, rate of excretion, drug combination (i.e., other drugsbeing administered to the patient) and the severity of the particulardisease undergoing therapy, as well as the judgment of the prescribingmedical practitioner. In general, the use of the minimum dose sufficientto provide effective therapy is preferred. Patients may generally bemonitored for therapeutic effectiveness using medical or veterinarycriteria suitable for the condition being treated or prevented.

Dosage levels of the order of from about 0.1 mg to about 140 mg perkilogram of body weight per day are useful in the treatment orpreventions of conditions involving pathogenic C5a activity (about 0.5mg to about 7 g per human patient per day). The amount of activeingredient that may be combined with the carrier materials to produce asingle dosage form will vary depending upon the host treated and theparticular mode of administration. Dosage unit forms will generallycontain between from about 1 mg to about 500 mg of an active ingredient.For compounds administered orally, transdermally, intravaneously, orsubcutaneously, it is preferred that sufficient amount of the compoundbe administered to achieve a serum concentration of 5 ng(nanograms)/mL-10 μg (micrograms)/mL serum, more preferably sufficientcompound to achieve a serum concentration of 20 ng-1 μg/ml serum shouldbe administered, most preferably sufficient compound to achieve a serumconcentration of 50 ng/ml-200 ng/ml serum should be administered. Fordirect injection into the synovium (for the treatment of arthritis)sufficient compounds should be administered to achieve a localconcentration of approximately 1 micromolar.

Frequency of dosage may also vary depending on the compound used and theparticular disease treated. However, for treatment of most disorders, adosage regimen of 4 times daily, three times daily, or less ispreferred, with a dosage regimen of once daily or 2 times daily beingparticularly preferred. It will be understood, however, that thespecific dose level for any particular patient will depend upon avariety of factors including the activity of the specific compoundemployed, the age, body weight, general health, sex, diet, time ofadministration, route of administration, and rate of excretion, drugcombination (i.e., other drugs being administered to the patient), theseverity of the particular disease undergoing therapy, and otherfactors, including the judgment of the prescribing medical practitioner.

Combination Therapy

The presently disclosed compounds may be used in combination with one ormore additional therapeutic agents that are used in the treatment,prevention, suppression or amelioration of the diseases or conditionsfor which compounds and compositions of the present invention areuseful. Such one or more additional therapeutic agents may beadministered, by a route and in an amount commonly used therefor,contemporaneously or sequentially with a compound or composition of thepresent invention. When a compound or composition of the presentinvention is used contemporaneously with one or more other drugs, apharmaceutical composition containing such other drugs in addition tothe compound or composition of the present invention is preferred.Accordingly, the pharmaceutical compositions of the present inventioninclude those that also contain one or more other active ingredients ortherapeutic agents, in addition to a compound or composition of thepresent invention.

Examples of the one or more additional therapeutic agents arecorticosteroids, steroids, immunosuppressants, Immunoglobulin Gagonists, Dipeptidyl peptidase IV inhibitors, Lymphocyte functionantigen-3 receptor antagonists, Interleukin-2 ligands, Interleukin-1beta ligand inhibitors, IL-2 receptor alpha subunit inhibitors, HGF genestimulators, IL-6 antagonists, IL-5 antagonists, Alpha 1 antitrypsinstimulators, Cannabinoid receptor antagonists, Histone deacetylaseinhibitors, AKT protein kinase inhibitors, CD20 inhibitors, Abl tyrosinekinase inhibitors, JAK tyrosine kinase inhibitors, TNF alpha ligandinhibitors, Hemoglobin modulators, TNF antagonists, proteasomeinhibitors, CD3 modulators, Hsp 70 family inhibitors, Immunoglobulinagonists, CD30 antagonists, tubulin antagonists, Sphingosine-1-phosphatereceptor-1 agonists, connective tissue growth factor ligand inhibitors,caspase inhibitors, adrenocorticotrophic hormone ligands, Btk tyrosinekinase inhibitors, Complement C1s subcomponent inhibitors,Erythropoietin receptor agonists, B-lymphocyte stimulator ligandinhibitors, Cyclin-dependent kinase-2 inhibitors, P-selectinglycoprotein ligand-1 stimulators, mTOR inhibitors, Elongation factor 2inhibitors, Cell adhesion molecule inhibitors, Factor XIII agonists,Calcineurin inhibitors, Immunoglobulin G1 agonists, Inosinemonophosphate dehydrogenase inhibitors, Complement C1s subcomponentinhibitors, Thymidine kinase modulators, Cytotoxic T-lymphocyteprotein-4 modulators, Angiotensin II receptor antagonists, AngiotensinII receptor modulators, TNF superfamily receptor 12A antagonists, CD52antagonists, Adenosine deaminase inhibitors, T-cell differentiationantigen CD6 inhibitors, FGF-7 ligands, dihydroorotate dehydrogenaseinhibitors, Syk tyrosine kinase inhibitors, Interferon type I receptorantagonists, Interferon alpha ligand inhibitors, Macrophage migrationinhibitory factor inhibitors, Integrin alpha-V/beta-6 antagonists,Cysteine protease stimulators, p38 MAP kinase inhibitors, TP53 geneinhibitors, Shiga like toxin I inhibitors, Fucosyltransferase 6stimulators, Interleukin 22 ligands, IRS1 gene inhibitors, Proteinkinase C stimulators, Protein kinase C alpha inhibitors, CD74antagonists, Immunoglobulin gamma Fc receptor IIB antagonists, T-cellantigen CD7 inhibitors, CD95 antagonists, N acetylmannosamine kinasestimulators, Cardiotrophin-1 ligands, Leukocyte elastase inhibitors,CD40 ligand receptor antagonists, CD40 ligand modulators, IL-17antagonists, TLR-2 antagonists, Mannan-binding lectin serine protease-2(MASP-2) inhibitors, Factor B inhibitors, Factor D inhibitors, C3aRmodulators, C5aR2 modulators, T cell receptor antagonists, PD-1inhibitors, PD-L1 inhibitors, TIGIT inhibitors, TIM-3 inhibitors, LAG-3inhibitors, VISTA inhibitors, STING agonists, IDO inhibitors, adenosinereceptor modulators, CD39 inhibitors, CD73 inhibitors, antagonists ofthe chemokine receptors, especially CXCR1, CXCR2, CXCR3, CXCR4, CXCR7,CCR1, CCR2, CCR3, CCR4, CCR5, CCR7, CCR7, CCR9, CX3CR1 and CXCR6, andcombinations thereof.

In some embodiments, the additional therapeutic agent used in thetherapeutic methods herein, is selected from the group consisting ofobinutuzumab, rituximab, ocrelizumab, cyclophosphamide, prednisone,hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortolpivalate, prednisolone, methylprednisolone, triamcinolone acetonide,triamcinolone alcohol, mometasone, amcinonide, budesonide, desonide,fluocinonide, fluocinolone acetonide, halcinonide, betamethasone,betamethasone sodium phosphate, dexamethasone, dexamethasone sodiumphosphate, fluocortolone, hydrocortisone-17-valerate, halometasone,alclometasone dipropionate, beclomethasone, betamethasone valerate,betamethasone dipropionate, prednicarbate, clobetasone-17-butyrate,clobetasol-17-propionate, fluocortolone caproate, fluocortolonepivalate, fluprednidene acetate, hydrocortisone-17-butyrate,hydrocortisone-17-aceponate, hydrocortisone-17-buteprate, ciclesonideand prednicarbate, GB-0998, immuglo, begelomab, alefacept, aldesleukin,gevokizumab, daclizumab, basiliximab, inolimomab, beperminogeneperplasmid, sirukumab, tocilizumab, clazakizumab, mepolizumab,fingolimod, panobinostat, triciribine, nilotinib, imatinib, tofacitinib,momelotinib, peficitinib, itacitinib, infliximab, PEG-bHb-CO,etanercept, ixazomib, bortezomib, muromonab, otelixizumab, gusperimus,brentuximab vedotin, Ponesimod, KRP-203, FG-3019, emricasan,corticotropin, ibrutinib, cinryze, conestat, methoxy polyethyleneglycol-epoetin beta, belimumab, blisibimod, atacicept, seliciclib,neihulizumab, everolimus, sirolimus, denileukin diftitox, LMB-2,natalizumab, catridecacog, ciclosporin, tacrolimus, voclosporin,voclosporin, canakinumab, mycophenolate, mizoribine, CE-1145, TK-DLI,abatacept, belatacept, olmesartan medoxomil, sparsentan, TXA-127,BIIB-023, alemtuzumab, pentostatin, itolizumab, palifermin, leflunomide,PRO-140, cenicriviroc, fostamatinib, anifrolumab, sifalimumab, BAX-069,BG-00011, losmapimod, QPI-1002, ShigamAbs, TZ-101, F-652, reparixin,ladarixin, PTX-9908, aganirsen, APH-703, sotrastaurin, sotrastaurin,milatuzumab, SM-101, T-Guard, APG-101, DEX-M74, cardiotrophin-1,tiprelestat, ASKP-1240, BMS-986004, HPH-116, KD-025, OPN-305, TOL-101,defibrotide, pomalidomide, Thymoglobulin, laquinimod, remestemcel-L,Equine antithymocyte immunoglobulin, Stempeucel, LIV-Gamma, Octagam 10%,t2c-001, 99mTc-sestamibi, Clairyg, Prosorba, pomalidomide, laquinimod,teplizumab, FCRx, solnatide, foralumab, ATIR-101, BPX-501, ACP-01,ALLO-ASC-DFU, irbesartan+propagermanium, ApoCell, cannabidiol, RGI-2001,saratin, anti-CD3 bivalent antibody-diphtheria toxin conjugate, NOX-100,LT-1951, OMS721, ALN-CCS, ACH-4471, AMY-101, Acthar gel, and CD4+CD25+regulatory T-cells, MEDI7814, P32, P59, pembrolizumab, nivolumab,atezolizumab, avelumab, durvalumab, CCX354, CCX721, CCX9588, CCX140,CCX872, CCX598, CCX6239, CCX587, CCX624, CCX282, CCX025, CCX507, CCX430,CCX765, CCX758, CCX771, CCX662, CCX650, and combinations thereof.

The disease or disorder being treated will determine which additionaltherapeutic agent or therapeutic agents are most appropriatelyadministered in combination with the compounds of the presentinvention—such determination can be made by a person of skill in theart.

The weight ratio of the compound of the present invention to the secondactive ingredient may be varied and will depend upon the effective doseof each ingredient. Generally, an effective dose of each will be used.Thus, for example, when a compound of the present invention is combinedwith an NSAID the weight ratio of the compound of the present inventionto the NSAID will generally range from about 1000:1 to about 1:1000,preferably about 200:1 to about 1:200. Combinations of a compound of thepresent invention and other active ingredients will generally also bewithin the aforementioned range, but in each case, an effective dose ofeach active ingredient should be used.

Non-Pharmaceutical Applications

In another aspect of the invention, the compounds of the invention canbe used in a variety of non-pharmaceutical in vitro and in vivoapplication. For example, the compounds of the invention may be labeledand used as probes for the detection and localization of C5a receptor(cell preparations or tissue sections samples). The compounds of theinvention may also be used as positive controls in assays for C5areceptor activity, i.e., as standards for determining the ability of acandidate agent to bind to C5a receptor, or as radiotracers for positronemission tomography (PET) imaging or for single photon emissioncomputerized tomography (SPECT). Such methods can be used tocharacterize C5a receptors in living subjects. For example, a C5areceptor modulator may be labeled using any of a variety of well knowntechniques (e.g., radiolabeled with a radionuclide such as tritium), andincubated with a sample for a suitable incubation time (e.g., determinedby first assaying a time course of binding). Following incubation,unbound compound is removed (e.g., by washing), and bound compounddetected using any method suitable for the label employed (e.g.,autoradiography or scintillation counting for radiolabeled compounds;spectroscopic methods may be used to detect luminescent groups andfluorescent groups). As a control, a matched sample containing labeledcompound and a greater (e.g., 10-fold greater) amount of unlabeledcompound may be processed in the same manner. A greater amount ofdetectable label remaining in the test sample than in the controlindicates the presence of C5a receptor in the sample. Detection assays,including receptor autoradiography (receptor mapping) of C5a receptor incultured cells or tissue samples may be performed as described by Kuharin sections 8.1.1 to 8.1.9 of Current Protocols in Pharmacology (1998)John Wiley & Sons, New York.

The compounds provided herein may also be used within a variety of wellknown cell separation methods. For example, modulators may be linked tothe interior surface of a tissue culture plate or other support, for useas affinity ligands for immobilizing and thereby isolating, C5areceptors (e.g., isolating receptor-expressing cells) in vitro. In onepreferred application, a modulator linked to a fluorescent marker, suchas fluorescein, is contacted with the cells, which are then analyzed (orisolated) by fluorescence activated cell sorting (FACS).

EXAMPLES

The following examples are offered to illustrate, but not to limit theclaimed invention.

Reagents and solvents used below can be obtained from commercial sourcessuch as Aldrich Chemical Co. (Milwaukee, Wis., USA). ¹H-NMR spectra wererecorded on a Varian Mercury 400 MHz NMR spectrometer. Significant peaksare provided relative to TMS and are tabulated in the order:multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m,multiplet) and number of protons. Mass spectrometry results are reportedas the ratio of mass over charge, followed by the relative abundance ofeach ion (in parenthesis). In the examples, a single m/e value isreported for the M+H (or, as noted, M−H) ion containing the most commonatomic isotopes. Isotope patterns correspond to the expected formula inall cases. Electrospray ionization (ESI) mass spectrometry analysis wasconducted on a Hewlett-Packard MSD electrospray mass spectrometer usingthe HP1100 HPLC for sample delivery. Normally the analyte was dissolvedin methanol at 0.1 mg/mL and 1 microliter was infused with the deliverysolvent into the mass spectrometer, which scanned from 100 to 1500daltons. All compounds could be analyzed in the positive ESI mode, usingacetonitrile/water with 1% formic acid as the delivery solvent. Thecompounds provided below could also be analyzed in the negative ESImode, using 2 mM NH₄OAc in acetonitrile/water as delivery system.

The following abbreviations are used in the Examples and throughout thedescription of the invention:

-   EtOH: Ethanol-   EtONa: Sodium ethoxide-   THF: Tetrahydrofuran-   TLC: Thin layer chromatography-   MeOH: Methanol

Compounds within the scope of this invention can be synthesized asdescribed below, using a variety of reactions known to the skilledartisan. One skilled in the art will also recognize that alternativemethods may be employed to synthesize the target compounds of thisinvention, and that the approaches described within the body of thisdocument are not exhaustive, but do provide broadly applicable andpractical routes to compounds of interest.

Certain molecules claimed in this patent can exist in differentenantiomeric and diastereomeric forms and all such variants of thesecompounds are claimed.

The detailed description of the experimental procedures used tosynthesize key compounds in this text lead to molecules that aredescribed by the physical data identifying them as well as by thestructural depictions associated with them.

Those skilled in the art will also recognize that during standard workup procedures in organic chemistry, acids and bases are frequently used.Salts of the parent compounds are sometimes produced, if they possessthe necessary intrinsic acidity or basicity, during the experimentalprocedures described within this patent.

Synthesis of intermediate 1:3-(6-chloro-7-methoxy-1H-indol-4-yl)-2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine

Caution: Diazonium Formation could be Potentially Dangerous, PleaseHandle with Care and Wear Proper Personal Protective Equipment!

Step a: To a 250 mL flask charged with 90 mL of concentratedhydrochloric acid under magnetic stirring was added 2,6-diethylaniline(10.0 g, 67.0 mmol). The resulting mixture was stirred for 30 min andcooled with an ice-salt bath until the internal temperature reached−5°C. A solution of sodium nitrite (5.5 g, 80.0 mmol) in water (60 mL) wasadded slowly to the above mixture while maintaining the internaltemperature below 5° C.

Separately, tin(II) chloride dihydrate (31.6 g, 140.0 mmol) was added toa 500 mL 3-neck round bottom flask charged with concentratedhydrochloric acid (60 mL) under mechanical stirring. The resultingsolution was then cooled with an ice bath.

The diazonium slurry was then filtered into the 500 mL flask containingthe cooled tin chloride solution with vigorous stirring. After 90 min,the reaction mixture was transferred to a 500 mL Erlenmeyer flask andthe flask was rinsed with water (20 mL) and chloroform (8 mL). Thecombined mixture was stirred overnight at room temperature. The entireliquid layer was decanted to give a wet solid. The recovered materialwas dried in vacuo for one day and then transferred to a 500 mL 3-neckround bottom flask equipped with an overhead mechanical stirrer andstirred with ether (180 mL). The resulting mixture was cooled in an icebath, and NaOH solution (10 N, 30 mL) was added slowly to the abovemixture while maintaining the inner temperature below 12° C. After theaddition, the mixture was allowed to stand for 2 h on ice. The etherlayer was decanted into a 500 mL flask and a stream of hydrogen chloridegas was bubbled into the ether solution while stirring. The resultingprecipitate was collected by filtration to afford(2,6-diethylphenyl)hydrazine hydrochloride. MS: (ES) m/z calculated forC₁₀H₁₇N₂ [M+H]⁺ 165.1, found 165.1.

Step b: N,N-diisopropylethylamine (8 mL, 46.0 mmol) was added to amixture of (2,6-diethylphenyl)hydrazine hydrochloride (8 g, 39.9 mmol),tert-butyl 3-cyano-4-oxopiperidine-1-carboxylate (5 g, 22.3 mmol) andEtOH (60 mL) in a 250 mL round bottom flask under magnetic stirring. Theresulting mixture was stirred under reflux for 3 h. Glacial acetic acid(12 mL, 208 mmol) was added and the mixture was stirred under reflux foranother 2 h. The solvent was removed under reduced pressure and theresidue was dissolved in EtOAc and washed with NaOH solution (2 N),brine, and dried over MgSO₄. The solvent was removed under reducedpressure and the residue was purified by silica gel flash chromatography(5 to 55% EtOAc in hexanes) to give tert-butyl3-amino-2-(2,6-diethylphenyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate.MS: (ES) m/z calculated for C₂₁H₃₁N₄O₂ [M+H]⁺ 371.2, found 371.2.

Caution: Diazonium Formation could be Potentially Dangerous, PleaseHandle with Care and Wear Proper Personal Protective Equipment!

Isopentyl nitrite (4 mL, 28.6 mmol) was added slowly at room temperatureto a mixture of tert-butyl3-amino-2-(2,6-diethylphenyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(3 g, 8.1 mmol), CuBr (4 g, 27.9 mmol) and MeCN (50 mL) in a 250 mLround bottom flask under magnetic stirring. The resulting mixture wasstirred at room temperature for 1 h, diluted with EtOAc, filteredthrough Celite, washed with saturated NH₄Cl solution, and dried overMgSO₄. The solvent was removed under reduced pressure and the residuewas purified by silica gel flash chromatography (2 to 25% EtOAc inhexanes) to give tert-butyl3-bromo-2-(2,6-diethylphenyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate.MS: (ES) m/z calculated for C₂₁H₂₉BrN₃O₂ [M+H]⁺ 434.1, found 434.2.

Step c: Iodomethane (1.5 mL, 24 mmol) was added to a suspension of4-bromo-2-chloro-6-nitrophenol (3.2 g, 12.7 mmol) and K₂CO₃ (3 g, 21.7mmol) in DMF (40 mL) in a 250 mL round bottom flask under magneticstirring. The resulting mixture was stirred at 45° C. for 4 h, dilutedwith EtOAc, washed with brine, and dried over MgSO₄. The solvent wasremoved under reduced pressure and the residue was purified by silicagel flash chromatography (2 to 25% EtOAc in hexanes) to give5-bromo-1-chloro-2-methoxy-3-nitrobenzene. MS: (ES) m/z calculated forC₇H₆BrClNO₃ [M+H]⁺ 265.9, found 265.9.

A solution of vinylmagenesium bromide in THF (1 M, 40 mL, 40 mmol) wasadded rapidly to a solution of 5-bromo-1-chloro-2-methoxy-3-nitrobenzene(3.2 g, 12 mmol) in anhydrous THF (40 mL) under N₂ and vigorous stirringat −60° C. The reaction mixture was allowed to warm to −30° C. over 1.5h. The reaction was quenched with saturated aqueous NH₄Cl solution andthe mixture was allowed to warm up to room temperature over 1 h. Thereaction mixture was diluted with EtOAc, washed with brine and driedover MgSO₄. The solvent was removed under reduced pressure and theresidue was purified by silica gel flash chromatography (2 to 20% EtOAcin hexanes) to give 4-bromo-6-chloro-7-methoxy-1H-indole. MS: (ES) m/zcalculated for C₉H₈BrClNO [M+H]⁺ 259.9, found 259.9.

To a suspension of 4-bromo-6-chloro-7-methoxy-1H-indole (1.2 g, 4.6mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (2.4g, 9.5 mmol), and KOAc (2.3 g, 23.4 mmol) in DMSO (10 mL) was addedPd(dppf)Cl₂ complex with dichloromethane (600 mg, 0.73 mmol). Thereaction mixture was degassed (N₂) for 2 min and stirred at 120° C. for2 h. The reaction mixture was diluted with EtOAc, filtered throughCelite, washed with brine and dried over MgSO₄. The solvent was removedunder reduced pressure and the residue was purified by silica gel flashchromatography (5 to 20% EtOAc in hexanes) to give6-chloro-7-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole.MS: (ES) m/z calculated for C₁₅H₂₀BClNO₃ [M+H]⁺ 308.1, found 308.1.

To a suspension of tert-butyl3-bromo-2-(2,6-diethylphenyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(600 mg, 1.4 mmol),6-chloro-7-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole(550 mg, 1.8 mmol), and K₂CO₃ (500 mg, 3.6 mmol) in p-dioxane (6 mL) andH₂O (1 mL) was added Pd(dppf)Cl₂ complex with dichloromethane (300 mg,0.37 mmol). The reaction mixture was degassed (N₂) for 2 min and stirredunder N₂ at 100° C. for 2 h. The reaction mixture was diluted withEtOAc, filtered through Celite, washed with brine and dried over MgSO₄.The solvent was removed under reduced pressure and the residue waspurified by silica gel flash chromatography (5 to 20% EtOAc in hexanes)to give tert-butyl3-(6-chloro-7-methoxy-1H-indol-4-yl)-2-(2,6-diethylphenyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate.MS: (ES) m/z calculated for C₃₀H₃₆ClN₄O₃ [M+H]⁺ 535.2.1, found 535.2.

The above tert-butyl3-(6-chloro-7-methoxy-1H-indol-4-yl)-2-(2,6-diethylphenyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylatewas dissolved in dichloromethane (5 mL) and charged with 4 N HCl indioxane (5 mL, 20 mmol). The resulting mixture was stirred at roomtemperature for 2 h. After the reaction was complete, the solvent wasevaporated in vacuo to give3-(6-chloro-7-methoxy-1H-indol-4-yl)-2-(2,6-diethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridinehydrochloride. MS: (ES) m/z calculated for C₂₅H₂₉ClN₄O [M+H]⁺ 435.2,found 435.2.

Step d: N,N-diisopropylethylamine (0.2 mL, 1.15 mmol) was added to asuspension of3-(6-chloro-7-methoxy-1H-indol-4-yl)-2-(2,6-diethylphenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridinehydrochloride (100 mg, 0.21 mmol),2-chloro-5-(trifluoromethyl)pyrimidine (45 mg, 0.25 mmol), and Li₂CO₃(20 mg, 0.27 mmol) in MeCN (10 mL) under magnetic stirring. Theresulting mixture was stirred at 75° C. for 30 min. After cooling toroom temperature, the reaction mixture was diluted with EtOAc, washedwith brine and dried over MgSO₄. The solvent was removed under reducedpressure and the residue was purified by preparative TLC (40% EtOAc inhexanes) followed by trituration in MeOH to afford3-(6-chloro-7-methoxy-1H-indol-4-yl)-2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine.¹H NMR (400 MHz, CDCl₃) δ 8.48 (s, 2H), 8.46 (s, 1H), 7.06-7.27 (m, 4H),6.62 (d, J=1.0 Hz, 1H), 6.42-6.49 (m, 1H), 4.83 (s, 2H), 4.36 (t, J=5.7Hz, 2H), 4.00 (s, 3H), 3.03 (t, J=5.7 Hz, 2H), 2.10-2.40 (m, 4H),0.80-1.08 (m, 6H). MS: (ES) m/z calculated for C₃₀H₂₉ClF₃N₆O [M+H]⁺581.2, found 581.2.

Synthesis of intermediate 2:[4-[2-(2,6-diethylphenyl)-5-[5-(trifluoromethyl)pyrimidin-2-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl]-5-fluoro-1H-indol-7-yl]methanol

Step a: Vinylmagnesium bromide solution in THF (1 M, 341 mL, 341 mmol)was added to a solution of 4-bromo-5-fluoro-2-nitrobenzoic acid (15.0 g,56.8 mmol) in anhydrous THF (200 mL) under N₂ at −50° C. The reactionmixture was stirred at the same temperature and allowed to warm to −40°C. over 1.5 h. The reaction mixture was quenched with saturated aqueousNH₄Cl solution and allowed to warm up to room temperature over 1 h. Thereaction mixture was acidified with 1 N aqueous HCl, diluted with EtOAc,washed with brine and dried over Na₂SO₄. The solvent was removed underreduced pressure to give a crude residue.

The above crude residue was stirred in a mixture of H2504 (25 mL) inMeOH (250 mL) at reflux for 5 h. It was then cooled to room temperatureand concentrated under reduced pressure. The obtained residue wasdiluted with EtOAc and brine. The organic layer was separated, driedwith Na₂SO₄, concentrated under reduced pressure and purified by silicagel flash chromatography (0 to 50% EtOAc in hexanes) to give methyl4-bromo-5-fluoro-1H-indole-7-carboxylate. MS: (ES) m/z calculated forC₁₀H₈BrFNO₂ [M+H]⁺ 271.9, found 271.9.

To a suspension of methyl 4-bromo-5-fluoro-1H-indole-7-carboxylate(0.900 g, 3.3 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.51 g,5.94 mmol), and KOAc (1.62 g, 16.5 mmol) in DMSO (19 mL) was addedPd(dppf)Cl₂ complex with dichloromethane (400 mg, 0.49 mmol). Thereaction mixture was degassed (N₂) for 2 min and stirred at 115° C. for1.5 h. The reaction mixture was diluted with EtOAc, filtered throughCelite, washed with brine and dried over Na₂SO₄. The solvent was removedunder reduced pressure and the residue was purified by silica gel flashchromatography (0 to 100% CH₂Cl₂/hexanes) to give methyl5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxylate.MS: (ES) m/z calculated for C₁₆H₂₀BFNO₄ [M+H]⁺ 320.1, found 320.1.

To a suspension of tert-butyl3-bromo-2-(2,6-diethylphenyl)-6,7-dihydro-2H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate(1.00 g, 2.31 mmol), methyl5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxylate(740 mg, 2.31 mmol) and K₂CO₃ (1.28 g, 9.24 mmol) in p-dioxane (14 mL)and water (2.5 mL) was added Pd(dppf)Cl₂ complex with dichloromethane(400 mg, 0.49 mmol). The reaction mixture was degassed (N₂) for 2 minand stirred under N₂ at 100° C. for 2.5 h. The reaction mixture wasdiluted with EtOAc, washed with aqueous NaHCO₃ and dried over Na₂SO₄.The solvent was removed under reduced pressure and the residue waspurified by silica gel flash chromatography (0 to 70% EtOAc in hexanes)to give tert-butyl2-(2,6-diethylphenyl)-3-(5-fluoro-7-methoxycarbonyl-1H-indol-4-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate.MS: (ES) m/z calculated for C₃₁H₃₆FN₄O₄ [M+H]⁺ 547.2, found 547.2.

Step b: The above tert-butyl2-(2,6-diethylphenyl)-3-(5-fluoro-7-methoxycarbonyl-1H-indol-4-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(1.00 g, 1.83 mmol) was dissolved in THF (35 mL) and charged with asolution of LiAlH₄ in ether (1 M, 2.7 mL) at 0° C. The resulting mixturewas stirred at 0° C. for 40 min. It was then quenched with water,diluted with IPA/CHCl₃ (1:3), washed with brine and dried over Na₂SO₄.The solvent was removed under reduced pressure and the residue waspurified by silica gel flash chromatography (0 to 90% EtOAc in hexanes)to give tert-butyl2-(2,6-diethylphenyl)-3-[5-fluoro-7-(hydroxymethyl)-1H-indol-4-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate.MS: (ES) m/z calculated for C₃₀H₃₆FN₄O₃ [M+H]⁺ 519.2, found 519.2.

The above tert-butyl2-(2,6-diethylphenyl)-3-(5-fluoro-7-(hydroxymethyl)-1H-indol-4-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate(650 mg, 1.25 mmol) was dissolved in dichloromethane (13 mL) and chargedwith 4 N HCl in dioxane (35 mL, 140 mmol). The resulting mixture wasstirred at room temperature for 1.5 h. After the reaction was complete,the solvent was evaporated in vacuo to give[4-[2-(2,6-diethylphenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-5-fluoro-1H-indol-7-yl]methanolhydrochloride. MS: (ES) m/z calculated for C₂₅H₂₈FN₄O [M+H]⁺ 419.2,found 419.2.

Step c: Triethylamine (1.50 mL, 10.7 mmol) was added to a suspension of[4-[2-(2,6-diethylphenyl)-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridin-3-yl]-5-fluoro-1H-indol-7-yl]methanolhydrochloride (600 mg, 1.32 mmol) and2-chloro-5-(trifluoromethyl)pyrimidine (350 mg, 1.9 mmol) in MeCN (70mL). The resulting mixture was stirred at 80° C. for 30 min. Aftercooling to room temperature, the reaction mixture was diluted withEtOAc, washed with aqueous NaHCO₃ and dried over Na₂SO₄. The solvent wasremoved under reduced pressure and the residue was purified by silicagel flash chromatography (0 to 90% EtOAc in hexanes) to afford[4-[2-(2,6-diethylphenyl)-5-[5-(trifluoromethyl)pyrimidin-2-yl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-3-yl]-5-fluoro-1H-indol-7-yl]methanol.¹H NMR (400 MHz, CDCl₃) δ 9.05 (br s, 1H), 8.47 (br s, 2H), 7.27 (m,1H), 7.16 (m, 2H), 6.86 (d, J=7.26 Hz, 1H), 6.56 (d, J=10.0 Hz, 1H),6.37 (t, J=2.6 Hz, 1H), 4.88 (m, 3H), 4.68 (d, J=16.4 Hz, 1H), 4.43 (m,1H), 4.29 (m, 1H), 3.04 (t, J=6.0 Hz, 2H), 2.38-2.58 (m, 3H), 2.17(sextet, J=7.3 Hz, 1H), 1.94 (sextet, J=7.3 Hz, 1H), 1.21 (t, J=7.4 Hz,3H), 0.75 (t, J=7.4 Hz, 3H). MS: (ES) m/z calculated for C₃₀H₂₉F₄N₆O[M+H]⁺ 565.2, found 565.2.

Synthesis of intermediate 3:1-(4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-2,5-difluorophenyl)urea

Step a: Pyridine (4.0 mL, 49.5 mmol) was added to a mixture of(2,6-diethylphenyl)hydrazine hydrochloride (5.0 g, 24.9 mmol),tert-butyl 4-cyano-2,2-dimethyl-3-oxopyrrolidine-1-carboxylate (5.0 g,21.0 mmol) and EtOH (60 mL) in a 250 mL round bottom flask undermagnetic stirring. The resulting mixture was stirred at 70° C. for 24 h.The solvent was removed under reduced pressure, and the residue wasdiluted with EtOAc and washed with aqueous citric acid solution,saturated aqueous NaHCO₃ solution, brine, and dried over MgSO₄. Thesolvent was removed under reduced pressure and the residue wascrystallized from cyclohexane to give tert-butyl3-amino-2-(2,6-diethylphenyl)-6,6-dimethyl-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate.MS: (ES) m/z calculated for C₂₂H₃₃N₄O₂ [M+H]⁺385.2, found 385.2.

Caution: Diazonium Formation could be Potentially Dangerous, PleaseHandle with Care and Wear Proper Personal Protective Equipment!

Tert-butyl nitrite (0.5 mL, 3.8 mmol) was added slowly at roomtemperature to a mixture of tert-butyl3-amino-2-(2,6-diethylphenyl)-6,6-dimethyl-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate(1 g, 2.6 mmol), diiodomethane (1.5 mL, 18.6 mmol) and MeCN (15 mL) in a100 mL round bottom flask under magnetic stirring. The resulting mixturewas stirred at 45° C. for 3 h before it was diluted with toluene, washedwith saturated NH₄Cl solution/NH₄OH (3:1), brine, and dried over MgSO₄.The solvent was removed under reduced pressure and the residue waspurified by silica gel flash chromatography (2 to 25% EtOAc in hexanes)to give tert-butyl2-(2,6-diethylphenyl)-3-iodo-6,6-dimethyl-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate.MS: (ES) m/z calculated for C₂₂H₃₁IN₃O₂ [M+H]⁺ 496.1, found 496.2.

Step b: A mixture of 4-bromo-2,5-difluoroaniline (1.5 g, 7.2 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (2.2 g, 8.7mmol), KOAc (1.8 g, 18.3 mmol) and Pd(dppf)Cl₂ complex withdichloromethane (580 mg, 0.7 mmol) in dioxane (12 mL) was stirred at 95°C. for 2 h under nitrogen. The mixture was then cooled to roomtemperature and filtered over Celite. The filtrate was collected,concentrated under reduced pressure, and purified by silica gel flashchromatography (0 to 50% EtOAc in hexanes) to give2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline. MS:(ES) m/z calculated for C₁₂H₁₇BF₂NO₂ [M+H]⁺ 256.1, found 256.2.

To a suspension of tert-butyl2-(2,6-diethylphenyl)-3-iodo-6,6-dimethyl-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate(0.7 g, 1.4 mmol),2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.7g, 2.7 mmol), K₂CO₃ (1.3 g, 7.2 mmol) in dioxane (10 mL) and water (2mL) was added Pd(dppf)Cl₂ complex with dichloromethane (300.0 mg, 0.37mmol). The reaction mixture was degassed (N₂) for 2 min and stirredunder N₂ at 100° C. for 2 h. The reaction mixture was diluted withEtOAc, filtered through Celite, washed with brine, dried over MgSO₄, andfiltered. The solvent was removed under reduced pressure and the residuewas purified by silica gel flash chromatography (2 to 10% EtOAc inhexanes) to give tert-butyl3-(4-amino-2,5-difluorophenyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate.MS: (ES) m/z calculated for C₂₈H₃₅F₂N₄O₂ [M+H]⁺ 497.3, found 497.5.

Step c: A mixture of tert-butyl3-(4-amino-2,5-difluorophenyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate(0.5 g, 1.0 mmol) and benzoyl isocyanate (0.5 g, 3.4 mmol) in THF (10mL) was stirred for 3 h at room temperature. The mixture wasconcentrated under reduced pressure to obtain tert-butyl3-(4-(3-benzoylureido)-2,5-difluorophenyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate.

A mixture of tert-butyl3-(4-(3-benzoylureido)-2,5-difluorophenyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate(˜1.0 mmol, from above) and K₂CO₃ (1.3 g, 7.2 mmol) in MeOH (15 mL) wasstirred for 2 h at room temperature followed by 20 min at 50° C. Themixture was extracted with EtOAc. The organic layer was separated, driedover MgSO₄, concentrated under reduced pressure and purified by silicagel flash chromatography (10 to 50% EtOAc in hexanes) to affordtert-butyl2-(2,6-diethylphenyl)-3-(2,5-difluoro-4-ureidophenyl)-6,6-dimethyl-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate.MS: (ES) m/z calculated for C₂₉H₃₆F₂N₅O₃ [M+H]⁺ 540.3, found 540.3.

Step d: The above tert-butyl2-(2,6-diethylphenyl)-3-iodo-6,6-dimethyl-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylatewas dissolved in dichloromethane (10 mL) and charged with 4 N HCl indioxane (5 mL, 20 mmol). The resulting mixture was stirred at roomtemperature for 12 h. Upon completion, the solvent was evaporated invacuo to give1-(4-(2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-2,5-difluorophenyl)ureahydrochloride. MS: (ES) m/z calculated for C₂₄H₂₈F₂N₅O [M+H]⁺ 440.2,found 440.3.

Step e: N,N-diisopropylethylamine (0.2 mL, 1.2 mmol) was added to asuspension1-(4-(2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-2,5-difluorophenyl)ureahydrochloride (0.1 g, 0.2 mmol), and2,4-bis(trifluoromethyl)benzaldehyde (0.2 g, 0.8 mmol) in1,2-dichloroethane (10 mL) under magnetic stirring. After stirring atroom temperature for 10 min, NaBH(OAc)₃ (0.3 g, 1.4 mmol) was added inportions. The resulting mixture was stirred at 45° C. for 2 h. Aftercooling to room temperature, the reaction mixture was diluted withEtOAc, washed with aqueous NaHCO₃ solution, brine and dried over MgSO₄.The solvent was removed under reduced pressure and the residue waspurified by preparative TLC (50% EtOAc in hexanes) followed by HPLC(MeCN/H₂O, with 0.1% TFA) to give1-(4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-2,5-difluorophenyl)urea.¹H NMR (400 MHz, CDCl₃) δ 8.18 (d, J=8.3 Hz, 1H), 7.88-7.98 (m, 2H),7.75-7.83 (m, 1H), 7.31 (t, J=7.7 Hz, 1H), 7.14 (d, J=7.7 Hz, 2H),6.79-6.85 (br, 1H), 6.40 (dd, J=6.5, 12.1 Hz, 1H), 4.79 (s, 2H), 4.13(s, 2H), 3.74 (s, 2H), 2.20-2.34 (m, 4H), 1.51 (s, 6H), 1.06 (t, J=7.6Hz, 6H). MS: (ES) m/z calculated for C₃₃H₃₂F₈N₅O [M+H]⁺ 666.2, found666.2.

Synthesis of intermediate 4:4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indole

Step a: The above tert-butyl2-(2,6-diethylphenyl)-3-iodo-6,6-dimethyl-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylatewas dissolved in dichloromethane (10 mL) and charged with 4 N HCl indioxane (5 mL, 20 mmol). The resulting mixture was stirred at roomtemperature for 12 h. Upon completion, the solvent was evaporated invacuo to give2-(2,6-diethylphenyl)-3-iodo-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolehydrochloride. MS: (ES) m/z calculated for C₁₇H₂₃IN₃ [M+H]⁺ 396.1, found396.2.

N,N-diisopropylethylamine (0.3 mL, 1.73 mmol) was added to a suspensionof2-(2,6-diethylphenyl)-3-iodo-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolehydrochloride (680 mg, 1.57 mmol), and2,4-bis(trifluoromethyl)benzaldehyde (800 mg, 3.3 mmol) in1,2-dichloroethane (10 mL) under magnetic stirring. After stirring atroom temperature for 10 min, NaBH(OAc)₃ (800 mg, 3.77 mmol) was added inportions. The resulting mixture was stirred at 45° C. for 2 h. Aftercooling to room temperature, the reaction mixture was diluted withEtOAc, washed with aqueous NaHCO₃ solution, brine and dried over MgSO₄.The solvent was removed under reduced pressure and the residue waspurified by silica gel flash chromatography (2 to 25% EtOAc in hexanes)to give5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-3-iodo-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole.MS: (ES) m/z calculated for C₂₆H₂₇F₆IN₃ [M+H]⁺ 622.1, found 622.1.

Step b: To a suspension of 4-bromo-7-fluoro-1H-indole (1.00 g, 4.67mmol), bis(pinacolato)diboron (1.31 g, 5.14 mmol) and KOAc (1.15 g, 11.7mmol) in dioxane (15 mL) was added Pd(dppf)Cl₂ complex withdichloromethane (416 mg, 0.51 mmol). The reaction mixture was degassedwith N₂ for 2 min and stirred at 100° C. for 2 h. The reaction mixturewas cooled to room temperature, diluted with EtOAc, and filtered throughCelite. The solvent was removed under reduced pressure and the residuewas purified by silica gel flash chromatography (0 to 30% EtOAc inhexanes) to give7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole. MS:(ES) m/z calculated for C₁₄H₁₈I₃FNO₂ [M+H]⁺ 262.1, found 262.1.

A mixture of5-(2,4-bis(trifluoromethyl)benzyl)-3-iodo-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole(200 mg, 0.32 mmol),7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (150mg, 0.57 mmol), K₂CO₃ (276 mg, 2.0 mmol) and Pd(dppf)Cl₂ complex withdichloromethane (60 mg, 0.07 mmol) in dioxane (6 mL) and water (1 mL)was stirred at 100° C. for 5 h under N₂. The mixture was cooled to roomtemperature, diluted with EtOAc, and filtered through a plug of Celite.The filtrate was collected, concentrated in vacuo and the residue waspurified by silica gel flash chromatography (0 to 50% EtOAc in hexanes)to yield4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indole.¹H NMR (400 MHz, CDCl₃) δ 8.44 (s, 1H), 8.19 (d, J=8.0 Hz, 1H), 7.86 (s,1H), 7.75 (d, J=8.4 Hz, 1H), 7.22 (m, 2H), 7.07 (d, J=7.6 Hz, 2H), 6.61(m, 1H), 6.47 (m, 2H), 4.15 (s, 2H), 3.71 (s, 2H), 2.37 (m, 2H), 2.22(m, 2H), 1.56 (s, 6H), 1.00 (t, J=7.6 Hz, 6H). MS: (ES) m/z calculatedfor C₃₄H₃₂F₇N₄ [M+H]⁺ 629.2, found 629.2.

Example 1: Synthesis of (phosphonooxy)methyl4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indole-1-carboxylate

Step a: To a stirred solution of4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indole(240 mg, 0.35 mmol) in DMF was added NaH (60%, 60 mg, 1.5 mmol) at 0° C.The mixture was stirred at 0° C. for 10 min, followed by addition ofdibenzyloxyphosphoryloxymethyl carbonochloridate (263 mg, 0.71 mmol) at0° C. The resulting mixture was stirred and allowed to warm up to roomtemperature over 30 min. After completion of the reaction, the reactionwas quenched with water, extracted with EtOAc, dried over Mg₂SO₄ andconcentrated in vacuo. The crude product was purified by silica gelchromatography (10 to 50% EtOAc in hexanes) to give((bis(benzyloxy)phosphoryl)oxy)methyl4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indole-1-carboxylate.MS: (ES) m/z calculated for C₅₀H₄₇F₇N₄O₆P [M+H]⁺ 963.3, found 963.3.

Step b: To a solution of ((bis(benzyloxy)phosphoryl)oxy)methyl4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indole-1-carboxylate(79 mg, 0.08 mmol) in ethyl acetate (40 mL) was added 10% Pd/C (100 mg),and hydrogenated under 45 psi for 20 min. The reaction mixture wasfiltered through Celite, rinsed with 1:1 EtOAc/MeOH (15 mL), andconcentrated to dryness. The residue was purified by HPLC (MeCN/H₂O,with 0.1% TFA) to give (phosphonooxy)methyl4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indole-1-carboxylate.¹H NMR (400 MHz, d₆-DMSO) δ 8.13 (d, J=8.2 Hz, 1H), 8.01 (d, J=8.2 Hz,1H), 7.95 (s, 1H), 7.80 (d, J=4.8 Hz, 1H), 7.30 (t, J=7.8 Hz, 1H), 7.12(d, J=7.8 Hz, 2H), 6.95 (dd, J=8.6, 12.1 Hz, 1H), 6.56-6.66 (m, 2H),5.70 (d, J=14.4 Hz, 2H), 4.15 (s, 2H), 3.60 (s, 2H), 3.35 (br, 2H),2.14-2.22 (m, 4H), 1.47 (s, 6H), 0.90 (t, J=7.6 Hz, 6H). MS: (ES) m/zcalculated for C₃₆H₃₅F₇N₄O₆P [M+H]⁺ 783.2, found 783.2.

Example 2: Synthesis of(S)-(4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indol-1-yl)-L-cysteine

Step a: To a stirred solution of di-tert-butyl3,3′-disulfanediyl(2R,2′R)-bis(2-((tert-butoxycarbonyl)amino)propanoate)(830 mg, 1.5 mmol) in dichloroethane (6 mL) at 0° C. was added thionylchloride (0.14 mL, 1.9 mmol). The mixture was stirred at 0° C. for 15min to form tert-butyl N-(tert-butoxycarbonyl)-S-chloro-L-cysteinatewhich was used directly in the next step.

To a stirred solution of4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indole(240 mg, 0.35 mmol) in THF (10 mL) under N₂ at −45° C. was added 1 MLiHMDS solution in THF (0.8 mL, 0.8 mmol). After stirring for 15 min at−45° C., tert-butyl N-(tert-butoxycarbonyl)-S-chloro-L-cysteinate formedabove (˜1.5 mmol) was added. The resulting mixture was stirred andallowed to warm to room temperature over 30 min. After completion, thereaction was quenched with water, extracted with EtOAc, dried over MgSO₄and concentrated in vacuo. The crude product was purified by silica gelchromatography (10 to 50% EtOAc in hexanes) to give tert-butyl(S)-(4-(5-(2,4-(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indol-1-O—N-(tert-butoxycarbonyl)-L-cysteinate.MS: (ES) m/z calculated for C₄₆H₅₃F₇N₅O₄S [M+H]⁺ 904.4, found 904.5.

Step b: To a solution of tert-butyl(S)-(4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indol-1-yl)-N-(tert-butoxycarbonyl)-L-cysteinate(220 mg, 0.24 mmol) in dichloromethane (6 mL) was added 4 N HCl indioxane (5 mL, 20 mmol). The resulting mixture was stirred at roomtemperature overnight. After completion, the mixture was concentrated invacuo. The residue was by HPLC (MeCN/H₂O, with 0.1% TFA) to give(S)-(4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indol-1-yl)-L-cysteine.¹H NMR (400 MHz, CD₃OD) δ 8.24 (d, J=7.6 Hz, 1H), 7.98-8.10 (m, 2H),7.63-7.66 (m, 2H), 7.22-7.37 (m, 2H), 6.97-7.03 (m, 1H), 6.63-6.68 (m,1H), 6.43-6.47 (m, 1H), 4.71-4.86 (m, 5H), 4.07-4.27 (m, 3H), 3.14-3.33(m, 2H), 2.37-2.49 (m, 2H), 2.02-2.26 (m, 2H), 1.85-1.94 (m, 6H),1.25-1.42 (m, 3H), 0.77-0.84 (m, 3H). MS: (ES) m/z calculated forC₃₇H₃₇F₇N₅O₂S [M+H]⁺ 748.3, found 748.2.

Example 3: Synthesis of(4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indol-1-yl)phosphonicacid

Step a: To a stirred solution of2-(2,6-diethylphenyl)-3-(6-fluoro-7-methoxy-1H-indol-4-yl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine(230 mg, 0.4 mmol) in THF (10 mL) under N₂ at −70° C. was added 1 MLiHMDS solution in THF (0.6 mL, 0.6 mmol). After stirring 15 min at −70°C., diethyl phosphorochloridate (0.1 mL, 0.8 mmol) was added. Theresulting mixture was allowed to warm to room temperature over 1 h.After completion, the mixture was quenched with water, extracted withEtOAc, washed with saturated aqueous NaHCO₃ solution, dried over MgSO₄and concentrated in vacuo. The crude product was purified by silica gelchromatography (5 to 25% EtOAc in hexanes) to give diethyl(4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indol-1-yl)phosphonate.MS: (ES) m/z calculated for C₃₄H₃₈F₄N₆O₄P [M+H]⁺ 701.3, found 701.3.

Step b: To a solution of diethyl(4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indol-1-yl)phosphonate(75 mg, 0.11 mmol) in dichloromethane (6 mL) at 0° C. was added TMSBr(0.2 mL, 1.5 mmol). The resulting mixture was allowed to warm to roomtemperature over 1 h, and then stirred at 40° C. overnight. Aftercompletion, the reaction mixture was concentrated in vacuo. The residuewas purified by HPLC (MeCN/H₂O, with 0.1% TFA) to give(4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indol-1-yl)phosphonicacid. ¹H NMR (400 MHz, CD₃OD) δ 8.58 (s, 2H), 7.68 (dd, J=2.5, 3.5 Hz,1H), 7.32 (t, J=7.7 Hz, 1H), 7.16 (br, 2H), 6.49-6.57 (m, 2H), 4.82-4.90(m, 4H), 4.39 (s, 2H), 3.99 (s, 3H), 2.98 (t, J=5.9 Hz, 2H), 2.05-2.42(m, 4H), 0.78-1.25 (m, 6H). MS: (ES) m/z calculated for C₃₀H₃₀F₄N₆O₄P[M+H]⁺ 645.2, found 645.4.

Example 4: Synthesis of (phosphonooxy)methyl4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indole-1-carboxylate

Step a: To a stirred solution of2-(2,6-diethylphenyl)-3-(6-fluoro-7-methoxy-1H-indol-4-yl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine(570 mg, 1.0 mmol) in DMF was added NaH (60%, 60 mg, 1.5 mmol) at 0° C.The mixture was stirred at 0° C. for 10 min, followed by addition ofdibenzyloxyphosphoryloxymethyl carbonochloridate (526 mg, 1.42 mmol).The resulting mixture was stirred and allowed to warm to roomtemperature over 30 min. After completion, the mixture was quenched withwater, extracted with EtOAc, dried over MgSO₄ and concentrated in vacuo.The crude product was purified by silica gel chromatography (10 to 100%EtOAc in hexanes) to give ((bis(benzyloxy)phosphoryl)oxy)methyl4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indole-1-carboxylate.MS: (ES) m/z calculated for C₄₆H₄₄F₄N₆O₇P [M+H]⁺ 899.3, found 899.3.

Step b: To a solution of ((bis(benzyloxy)phosphoryl)oxy)methyl4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indole-1-carboxylate(120 mg, 0.13 mmol) in ethyl acetate (45 mL) was added 10% Pd/C (200mg), and hydrogenated under 50 psi for 20 min. The reaction mixture wasfiltered through Celite, rinsed with 1:1 EtOAc/MeOH (15 mL),concentrated to dryness. The residue was purified by HPLC (MeCN/H₂O,with 0.1% TFA) to give (phosphonooxy)methyl4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indole-1-carboxylate.¹H NMR (400 MHz, CD₃OD) δ 8.58 (s, 2H), 7.87 (d, J=3.9 Hz, 1H), 7.33 (t,J=7.6 Hz, 1H), 7.16 (br s, 2H), 6.59-6.64 (m, 2H), 5.87 (d, J=14.4 Hz,2H), 4.74-4.86 (m, 4H), 4.39 (s, 2H), 3.97 (s, 3H), 2.98 (t, J=5.7 Hz,2H), 2.05-2.42 (m, 4H), 0.76-1.28 (m, 6H). MS: (ES) m/z calculated forC₃₂H₃₂F₄N₆O₇P [M+H]⁺ 719.2, found 719.2.

Example 5: Synthesis of(E)-4-(((4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indole-1-carbonyl)oxy)methoxy)-4-oxobut-2-enoicacid

Step a: To a stirred solution of2-(2,6-diethylphenyl)-3-(6-fluoro-7-methoxy-1H-indol-4-yl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine(280 mg, 0.5 mmol) in THF (10 mL) at −78° C. was added 1 M LiHMDSsolution in THF (0.8 mL, 0.8 mmol). The mixture was stirred at −78° C.for 15 min, followed by addition of chloromethyl carbonochloridate (804, 0.9 mmol). The resulting mixture was stirred and allowed to warm upto room temperature over 30 min. After completion, the mixture wasquenched with saturated aqueous NH₄Cl solution, extracted with EtOAc,dried over Mg₂SO₄ and concentrated in vacuo to give chloromethyl4-(2-(2,6-diethylphenyl)-5-(5-[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indole-1-carboxylate,which was directly in the next step. MS: (ES) m/z calculated forC₃₂H₃₀ClF₄N₆O₃ [M+H]⁺ 657.2, found 657.2.

Step a: NaI (350 mg, 2.33 mmol) was added to a stirred solution ofchloromethyl4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indole-1-carboxylate(300 mg, 0.46 mmol) in acetone (10 mL) at room temperature. Theresulting mixture was stirred at 45° C. overnight. After completion, themixture was quenched with brine, extracted with EtOAc, dried over MgSO₄and concentrated in vacuo. The crude product was purified by silica gelchromatography (5 to 25% EtOAc in hexanes) to give iodomethyl4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indole-1-carboxylate.MS: (ES) m/z calculated for C₃₂H₃₀F₄IN₆O₃ [M+H]⁺ 749.1, found 749.2.

Step c: To a solution of iodomethyl4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indole-1-carboxylate(50 mg, 0.07 mmol) in THF (5 mL) at 0° C. was added fumaric acidtetrabutylammonium salt (25 mg, 0.07 mmol) in DMF (1 mL). The resultingmixture was allowed to warm to room temperature over 1 h. Aftercompletion, the mixture was concentrated in vacuo. The residue waspurified by HPLC (MeCN/H₂O, with 0.1% TFA) to give(E)-4-(((4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indole-1-carbonyl)oxy)methoxy)-4-oxobut-2-enoicacid. ¹H NMR (400 MHz, CD₃OD) δ 8.58 (s, 2H), 7.87 (d, J=3.9 Hz, 1H),7.33 (t, J=7.6 Hz, 1H), 7.16 (br s, 2H), 6.59-6.64 (m, 2H), 5.87 (d,J=14.4 Hz, 2H), 4.74-4.86 (m, 4H), 4.39 (s, 2H), 3.97 (s, 3H), 2.98 (t,J=5.7 Hz, 2H), 2.05-2.42 (m, 4H), 0.76-1.28 (m, 6H). MS: (ES) m/zcalculated for C₃₆H₃₃F₄N₆O₇ [M+H]⁺ 737.2, found 737.2.

Example 6: Synthesis of ((dimethylglycyl)oxy)methyl4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indole-1-carboxylate

To a solution of iodomethyl4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indole-1-carboxylate(40 mg, 0.06 mmol) in MeCN (5 mL) at 0° C. was added tetrabutylammoniumdimethylglycinate (20 mg, 0.06 mmol) in DMF (1 mL). The resultingmixture was allowed to warm to room temperature over 1 h. Aftercompletion, the mixture was quenched with 1 N HCl (0.1 mL, 0.1 mmol) andpurified by HPLC (MeCN/H₂O, with 0.1% TFA) to give((dimethylglycyl)oxy)methyl4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indole-1-carboxylateas TFA salt. ¹H NMR (400 MHz, CD₃OD) δ 8.59 (s, 2H), 7.92 (d, J=3.9 Hz,1H), 7.34 (t, J=7.6 Hz, 1H), 7.17 (br s, 2H), 6.63-6.74 (m, 2H), 5.83(s, 2H), 4.81-4.88 (br s, 1H), 4.46 (s, 2H), 4.39 (s, 2H), 3.97 (s, 3H),3.45 (s, 5H), 2.95-3.03 (m, 5H), 2.05-2.42 (m, 4H), 0.76-1.28 (m, 6H).MS: (ES) m/z calculated for C₃₆H₃₈F₄N₇O₅ [M+H]⁺ 724.2, found 724.2.

Example 7: Synthesis of((4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-2,5-difluorophenyl)carbamoyl)phosphoramidicacid

Step a: To a solution of4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-2,5-difluoroaniline(100 mg, 0.16 mmol) in THF (6 mL) at −50° C. was addedphosphorisocyanatidic dichloride (0.04 mL, 0.41 mmol). The mixture wasallowed to warm to room temperature over 1 h and then concentrated invacuo. The residue was triturated with hexanes to to give((4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-2,5-difluorophenyl)carbamoyl)phosphoramidicdichloride which was used directly in the next step.

Step b: To a solution of the above((4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-2,5-difluorophenyl)carbamoyl)phosphoramidicdichloride (˜0.16 mmol) in THF (6 mL) at room temperature was addedwater (3 mL). The mixture was stirred at room temperature for 2 h,followed by addition of 1 N NaOH (0.5 mL, 0.5 mmol). The mixture wasstirred for another 2 h. After completion, the mixture was purified byHPLC (MeCN/H₂O, with 0.1% TFA) to yield((4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-2,5-difluorophenyl)carbamoyl)phosphoramidicacid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.60 (br, 1H), 8.29 (s, 1H), 8.16 (d,J=8.2 Hz, 2H), 7.92-8.08 (m, 2H), 7.38 (d, J=7.9 Hz, 1H), 7.21 (d, J=7.7Hz, 2H), 6.45 (dd, J=6.7, 11.9 Hz, 1H), 4.13 (s, 2H), 3.64 (s, 2H),3.24-3.48 (br, 2H), 2.16 (q, J=7.6 Hz, 4H), 1.42 (s, 6H), 0.95 (t, J=7.6Hz, 6H). MS: (ES) m/z calculated for C₃₃H₃₃F₈N₅O₄P [M+H]⁺ 746.2, found746.2.

Example 8: Synthesis of((3,3-dimethyl-5-(phosphonooxy)pentanoyl)oxy)methyl4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indole-1-carboxylate

Step a: To a flask containing 4,4-dimethyldihydro-2H-pyran-2,6(3H)-dione(5 g, 35 mmol) in THF (140 mL) was added dropwise a 1 M solution ofLiAlH₄ in THF (35 mL, 35 mmol). The mixture was heated at 75° C. for 2h. Upon was completion, the reaction was quenched with H₂O and themixture was filtered. The filtrate was concentrated to afford3,3-dimethylpentane-1,5-diol.

To a solution of 3,3-dimethylpentane-1,5-diol (1 g, 7.6 mmol) in THF(15.6 mL) was added dropwise a 1 M solution of tBuOK (8.3 mL, 8.3 mmol)followed by tetrabenzyldiphosphate (4.2 g, 7.8 mmol). After heating at70° C. for 16 h, the mixture was concentrated and purified by silica gelcolumn chromatography (0 to 100% EtOAc in hexanes) to yield dibenzyl(5-hydroxy-3,3-dimethylpentyl) phosphate. MS: (ES) m/z calculated forC₂₁H₂₉O₅P [M+H]⁺ 393.2, found 393.1.

To a solution of dibenzyl (5-hydroxy-3,3-dimethylpentyl) phosphate (400mg, 1 mmol), in DMF (10 mL) was added pyridinium dichromate (2.3 g, 6mmol). The mixture was stirred at room temperature of 2 h thenconcentrated and purified by silica gel column chromatography (0 to 100%EtOAc in hexanes). The purified residue was dissolved in 10 mL of a 1:1solution of tBuOH and H₂O. To the solution was added NaH₂PO₄ (0.61 g, 5mmol), followed by sodium chlorite (0.46 g, 5 mmol) and a 2 M solutionof 2-methyl-2-butene (5 mL, 10 mmol). The mixture was stirred at roomtemperature for 16 h. Upon completion, the mixture was concentrated invacuo and the crude residue was purified by silica gel columnchromatography (0 to 100% EtOAc in hexanes) to provide5-((bis(benzyloxy)phosphoryl)oxy)-3,3-dimethylpentanoic acid. MS: (ES)m/z calculated for C₂₁H₂₇O₆P [M+H]⁺ 407.2, found 407.1.

To a solution of iodomethyl4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indole-1-carboxylate(70 mg, 0.09 mmol) in 0.2 mL of DMF was added5-((bis(benzyloxy)phosphoryl)oxy)-3,3-dimethylpentanoic acid (54 mg,0.13 mmol) followed by Et₃N (0.02 mL, 0.14 mmol). The mixture wasstirred at room temperature for 2 h then concentrated in vacuo. Theresulting residue was purified by silica gel column chromatography (0 to100% EtOAc in hexanes) to produce(((5-((bis(benzyloxy)phosphoryl)oxy)-3,3-dimethylpentanoyl)oxy)methyl4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indole-1-carboxylate.

Step b: To a solution of(((5-((bis(benzyloxy)phosphoryl)oxy)-3,3-dimethylpentanoyl)oxy)methyl4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indole-1-carboxylate(50 mg, 0.05 mmol) in MeOH (1 mL) was added 10% Pd/C (6 mg, 0.005 mmol).The mixture was stirred under a H2 balloon for 1 h, then filteredthrough Celite, concentrated and purified by HPLC (MeCN/H₂O, with 0.1%TFA) to yield ((3,3-dimethyl-5-(phosphonooxy)pentanoyl)oxy)methyl4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indole-1-carboxylate.¹H NMR (400 MHz, CDCl₃) δ 8.54 (s, 2H), 7.63 (d, J=3.9 Hz, 1H), 7.28 (t,J=7.7 Hz, 1H), 7.08 (d, J=7.6 Hz, 2H), 6.59 (d, J=12.1 Hz, 1H), 6.47 (d,J=3.8 Hz, 1H), 6.02 (s, 2H), 5.60 (br s, 2H), 4.76 (bs, 2H), 4.38 (t,J=5.9 Hz, 2H), 4.03 (dd, J=14.1, 7.1 Hz, 2H), 3.99 (s, 3H), 3.10 (t,J=3.1 Hz, 2H), 2.35 (s, 2H), 2.20 (br s, 4H), 1.74 (t, J=7.0 Hz, 2H),1.05 (br s, 12H). MS: (ES) m/z calculated for C₃₉H₄₃FN₆O₉P [M+H]⁺ 847.3,found 847.2.

Example 9: Synthesis of (3-fluoro-4-phosphonooxyphenyl)methylN-((4-(5-((2,4-bis(trifluoromethyl)phenyl)methyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-4H-pyrrolo[3,4-c]pyrazol-3-yl)-2,5-difluorophenyl)carbamoyl]carbamate

Step a: To a solution of 3-fluoro-4-hydroxybenzaldehyde (5 g, 35.7 mmol)in dichloromethane (36 mL) was added Et₃N (7.5 mL, 53.8 mmol) followedby diethylchlorophosphate (5.7 mL, 39.4 mmol). The mixture was stirredat room temperature for 3 h then quenched with H₂O. The organic andaqueous layers were separated and the aqueous layer was extracted withEtOAc. The organic layers were combined, dried with sodium sulfate,filtered and concentrated in vacuo. The resultant residue was purifiedby silica gel column chromatography to afford diethyl(2-fluoro-4-formylphenyl) phosphate. MS: (ES) m/z calculated forC₁₁H₁₄FO₅P [M+H]⁺ 277.1, found 277.0.

To a solution of diethyl (2-fluoro-4-formylphenyl) phosphate (8.99 g,32.5 mmol) in THF (32.5 mL) at −78° C. was added NaBH₄ (3.6 g, 97.3mmol). After stirring at −78° C. for 1 h the reaction was quenched withH₂O. The organic and aqueous layers were separated and the aqueous layerwas extracted with EtOAc. The organic layers were combined, dried withsodium sulfate, filtered and concentrated in vacuo. The residue waspurified by silica gel column chromatography (85 to 100% EtOAc inhexanes) to produce diethyl (2-fluoro-4-(hydroxymethyl)phenyl)phosphate. MS: (ES) m/z calculated for C₁₁H₁₆FO₅P [M+H]⁺ 279.1, found279.0.

To a solution of diethyl (2-fluoro-4-(hydroxymethyl)phenyl) phosphate (1g, 3.6 mmol) in THF (8.7 mL) at 0° C. was added diisopropylethylamine(0.76 mL, 4.4 mmol) and triphosgene (0.53 g, 1.8 mmol). After stirringat 0° C. for 1 h, NH₄OH (1.6 mL, 41 mmol) was added. The mixture wasstirred at room temperature for 16 h then concentrated in vacuo and theresidue was purified by silica gel column chromatography (0 to 100%EtOAc in hexanes) to provide 4-((diethoxyphosphoryl)oxy)-3-fluorobenzylcarbamate. MS: (ES) m/z calculated for C₁₂H₁₇FNO₆P [M+H]⁺ 322.1, found322.0.

To a solution of 4-((diethoxyphosphoryl)oxy)-3-fluorobenzyl carbamate(155 mg, 0.48 mmol) in dichloromethane (4.8 mL) at 0° C. was addedoxalyl chloride (0.06 mL, 0.71 mmol). The mixture was heated at 40° C.for 16 h then concentrated in vacuo. The residue was dissolved in THF (2mL) and added to a solution of4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-2,5-difluoroaniline(100 mg, 0.16 mmol) in THF (2 mL). The mixture was stirred at roomtemperature for 5 h then concentrated in vacuo. The residue was purifiedby silica gel column chromatography (0 to 100% EtOAc in hexanes) to give(4-diethoxyphosphoryloxy-3-fluorophenyl)methylN-((4-(5-((2,4-bis(trifluoromethyl)phenyl)methyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-4H-pyrrolo[3,4-c]pyrazol-3-yl)-2,5-difluorophenyl)carbamoyl)carbamate.MS: (ES) m/z calculated for C₄₅H₄₅F₉N₅O₇P [M+H]⁺ 970.3, found 970.0.

Step b: To a solution of (4-diethoxyphosphoryloxy-3-fluorophenyl)methylN-((4-(5-((2,4-bis(trifluoromethyl)phenyl)methyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-4H-pyrrolo[3,4-c]pyrazol-3-yl)-2,5-difluorophenyl)carbamoyl)carbamate(77 mg, 0.08 mmol) in dichloromethane (1 mL) was added dropwise TMSBr(0.13 mL, 0.10 mmol). The mixture was stirred at room temperature for 16h then concentrated in vacuo. The residue was purified on HPLC(MeCN/H₂O, with 0.1% TFA) to yield (3-fluoro-4-phosphonooxyphenyl)methylN-44-(5-((2,4-bis(trifluoromethyl)phenyl)methyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-4H-pyrrolo[3,4-c]pyrazol-3-yl)-2,5-difluorophenyl)carbamoyl)carbamate.¹H NMR (400 MHz, CD₃OD) δ 8.22 (d, J=8.2 Hz, 1H), 8.15 (s, 1H),8.08-8.15 (m, 2H), 7.46 (dd, J=7.6, 7.9 Hz, 1H), 7.38 (dd, J=8.2, 8.2Hz, 1H), 7.28 (d, J=7.6 Hz, 2H), 7.17 (d, J=11.0 Hz, 1H), 7.10 (d, J=8.6Hz, 1H), 6.42 (dd, J=6.5, 11.5 Hz, 1H), 5.14 (s, 2H), 4.77 (s, 2H), 4.57(s, 2H), 3.34 (s, 2H), 2.24 (q, J=7.7 Hz, 4H), 1.89 (s, 6H), 1.05 (t,J=7.2 Hz, 6H). MS: (ES) m/z calculated for C₄₁H₃₇F₉N₅O₇P [M+H]⁺ 914.2,found 914.1.

Example 10: Synthesis of 3-nitro-4-(phosphonooxy)benzyl4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indole-1-carboxylate

Step a: To a solution of 4-hydroxy-3-nitrobenzaldehyde (1 g, 6.0 mmol)in dichloromethane (6 mL) was added Et₃N (1.25 mL, 9.0 mmol) anddiethylchlorophosphate (0.95 mL, 6.6 mmol). The mixture was stirred atroom temperature for 16 h then quenched with H₂O. The organic andaqueous layers were separated and the aqueous layer was extracted withEtOAc. The organic layers were combined, dried with sodium sulfate,filtered and concentrated in vacuo. The residue was purified by silicagel column chromatography (0 to 100% EtOAc in hexanes) to afford diethyl(4-formyl-2-nitrophenyl) phosphate. MS: (ES) m/z calculated forC₁₁H₁₄NO₇P [M+H]⁺ 304.1, found 304.0.

To a solution of diethyl (4-formyl-2-nitrophenyl) phosphate (1.36 g, 4.5mmol) in THF (4.5 mL) at −78° C. was added NaBH₄ (500 mg, 13.5 mmol).After stirring at −78° C. for 1 h the reaction was quenched with H₂O.The organic and aqueous layers were separated, and the aqueous layer wasextracted with EtOAc. The organic layers were combined, dried withsodium sulfate, filtered, and concentrated. The resultant residue waspurified by silica gel column chromatography (0 to 100% EtOAc inhexanes) to provide diethyl (4-(hydroxymethyl)-2-nitrophenyl)phosphate.MS: (ES) m/z calculated for C₁₁H₁₆NO₇P [M+H]⁺ 306.1, found 306.0.

To a solution of diethyl (4-(hydroxymethyl)-2-nitrophenyl)phosphate (100mg, 0.33 mmol) in THF (1.6 mL) at 0° C. was added diisopropylethylamine(0.07 mL, 0.40 mmol) and triphosgene (50 mg, 0.17 mmol). After stirringat 0° C. for 1 h, the reaction was quenched with H₂O. The organic andaqueous layers were separated, and the aqueous layer was extracted withEtOAc. The organic layers were combined, dried with sodium sulfate,filtered and concentrated to afford the crude chloroformateintermediate.

To a solution of2-(2,6-diethylphenyl)-3-(6-fluoro-7-methoxy-1H-indol-4-yl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine(93 mg, 0.16 mmol) in THF (1 mL) at 0° C. was added NaH (13 mg, 0.32mmol). After stirring at 0° C. for 30 min, a solution of the crudechloroformate (prepared above) in THF (0.5 mL), was added to themixture. The solution was stirred at room temperature for 16 h. Thereaction was quenched with H₂O. The organic and aqueous layers wereseparated, and the aqueous layer was extracted with EtOAc. The organiclayers were combined, dried with sodium sulfate, filtered andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (0 to 100% EtOAc in hexanes) to produce4-((diethoxyphosphoryl)oxy)-3-nitrobenzyl4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indole-1-carboxylate.

Step b: To a solution of 4-((diethoxyphosphoryl)oxy)-3-nitrobenzyl4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indole-1-carboxylate(128 mg, 0.14 mmol) in dichloromethane (1.4 mL) was added dropwise TMSBr(0.11 mL, 0.86 mmol). After stirring at room temperature for 5 h, anadditional amount of TMSBr (0.11 mL, 0.86 mmol) was added to themixture. The mixture was stirred at room temperature for 16 h,concentrated in vacuo and purified by HPLC (MeCN/H₂O, with 0.1% TFA) toyield 3-nitro-4-(phosphonooxy)benzyl4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indole-1-carboxylate.¹H NMR (400 MHz, DMSO-d₆) δ 8.68 (s, 2H), 8.12 (dd, J=0.9, 2.3 Hz, 1H),7.85 (d, J=3.8 Hz, 1H), 7.85 (dd, J=2.2, 8.6 Hz, 1H), 7.60 (dd, J=1.1,8.5 Hz, 1H), 7.29 (t, J=7.6 Hz, 1H), 7.12 (br s, 2H), 6.62 (d, J=3.8 Hz,1H), 6.55 (d, J=12.4 Hz, 1H), 5.48 (s, 2H), 4.76 (s, 2H), 4.30 (br s,2H), 3.83 (d, J=1.2 Hz, 3H), 2.91 (t, J=6.0 Hz, 2H), 2.16 (br s, 4H),2.04 (s, 2H), 0.91 (br s, 6H). MS: (ES) m/z calculated for C₃₈H₃₄FN₇O₉P[M+H]⁺ 840.2, found 840.0.

Example 11: Synthesis of 3-fluoro-4-(phosphonooxy)benzyl4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indole-1-carboxylate

Step a: To a solution of 3-fluoro-4-hydroxybenzaldehyde (1 g, 7.1 mmol)in THF (32 mL) was added a 1 M solution of tBuOK in THF (7.6 mL, 7.6mmol). The mixture was heated to 70° C. and tetrabenzylphosphate wasadded (4.0 g, 7.4 mmol). After 1 h at 70° C., hexanes was added to themixture and the contents were filtered. The filtrate was concentrated invacuo and the resulting residue was purified by silica gel columnchromatography (0 to 100% EtOAc in hexanes) to produce dibenzyl(2-fluoro-4-formylphenyl)phosphate. MS: (ES) m/z calculated forC₂₁H₁₈FO₅P [M+H]⁺ 401.1, found 401.1.

To a solution of dibenzyl (2-fluoro-4-formylphenyl) phosphate (2.68 g,6.7 mmol) in THF (6.7 mL) at −78° C. was added NaBH₄ (0.76 g, 20.5mmol). After stirring at −78° C. for 1 h, the mixture was quenched withH₂O. The organic and aqueous layers were separated, and the aqueouslayer was extracted with EtOAc. The combined organic layers were driedwith sodium sulfate, filtered and concentrated in vacuo. The resultingresidue was purified by silica gel column (0 to 100% EtOAc in hexanes)to provide dibenzyl (2-fluoro-4-(hydroxymethyl)phenyl)phosphate. MS:(ES) m/z calculated for C₂₁H₂₀FO₅P [M+H]⁺ 403.1, found 403.0.

To a solution of dibenzyl (2-fluoro-4-(hydroxymethyl)phenyl)phosphate(200 mg, 0.50 mmol) in THF (2.4 mL) at 0° C. was addeddiisopropylethylamine (0.1 mL, 0.57 mmol) and triphosgene (72 mg, 0.24mmol). After stirring at 0° C. for 1 h, the reaction was quenched withH₂O. The organic and aqueous layers were separated, and the aqueouslayer was extracted with EtOAc. The organic layers were combined, driedwith sodium sulfate, filtered and concentrated to afford the crudechloroformate intermediate.

To a solution of2-(2,6-diethylphenyl)-3-(6-fluoro-7-methoxy-1H-indol-4-yl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine(70 mg, 0.12 mmol) in THF (1.2 mL) at 0° C. was added NaH (10 mg, 0.24mmol). After stirring at 0° C. for 30 min, a solution of the crudechloroformate (prepared above) in THF (1.2 mL) was added to the mixture.The solution was stirred at 0° C. for 1 h then quenched with H₂O. Theorganic and aqueous layers were separated and the aqueous layer wasextracted with EtOAc. The organic layers were combined, dried withsodium sulfate, filtered and concentrated in vacuo. The residue waspurified by silica gel column chromatography (0 to 100% EtOAc inhexanes) to produce 4-((bis(benzyloxy)phosphoryl)oxy)-3-fluorobenzyl4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indole-1-carboxylate.

Step b: To a solution of4-((bis(benzyloxy)phosphoryl)oxy)-3-fluorobenzyl4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indole-1-carboxylate(100 mg, 0.10 mmol) in MeOH (1 mL) was added 10% Pd/C (10 mg, 0.01mmol). The mixture was stirred under a H2 balloon for 1 h, then filteredthrough Celite, concentrated and purified by HPLC (MeCN/H₂O, with 0.1%TFA) to yield 3-fluoro-4-(phosphonooxy)benzyl4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indole-1-carboxylate.¹H NMR (400 MHz, DMSO-d₆) δ 8.68 (s, 2H), 7.84 (s, 1H), 7.52-7.38 (m,2H), 7.37-7.25 (m, 2H), 7.11 (br s, 2H), 6.62 (s, 1H), 6.54 (d, J=12.3Hz, 1H), 5.40 (s, 2H), 4.76 (s, 2H), 4.30 (s, 2H), 3.83 (s, 3H), 2.90(bs, 2H), 2.16 (br s, 4H), 2.04 (br s, 2H), 0.90 (br s, 6H). MS: (ES)m/z calculated for C₃₈H₃₄F₅N₆O₇P [M+H]⁺ 813.2, found 813.2.

Example 12: Synthesis of (2-(4-(phosphonooxy)phenyl)acetoxy)methyl4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indole-1-carboxylate

Step a: To a flask containing ethyl 2-(4-hydroxyphenyl)acetate (1 g, 5.6mmol) in THF (11 mL) was added dropwise a 1 M solution of tBuOK in THF(5.9 mL, 5.9 mmol) and tetrabenzyldiphosphate (3 g, 5.6 mmol). Themixture was heated at 70° C. for 2 h. An additional amount of 1.0 MtBuOK (1.2 mL, 1.2 mmol) and tetrabenzyldiphosphate (0.6 g, 1.1 mmol)was added. The mixture was heated for an additional 3 h. Uponcompletion, hexanes was added and the contents were filtered. Thefiltrate was concentrated and the residue was purified by silica gelcolumn chromatography (0 to 100% EtOAc in hexanes) to afford ethyl2-(4-((bis(benzyloxy)phosphoryl)oxy)phenyl)acetate. MS: (ES) m/zcalculated for C₂₄H₂₅O₆P [M+H]⁺ 441.1, found 441.1.

To a solution of ethyl2-(4-((bis(benzyloxy)phosphoryl)oxy)phenyl)acetate (1.54 g, 3.5 mmol) inTHF (9 mL) was added dropwise a solution of LiOH (0.32 g, 7.6 mmol) inH₂O (9 mL). The mixture was stirred at room temperature for 1 h. Thereaction was quenched with 1 N HCl. The aqueous layer was extracted withEtOAc. The organic layers were combined, dried with sodium sulfate,filtered and concentrated. The residue was purified by silica gel columnchromatography (0 to 100% EtOAc in hexanes) to yield2-(4-((bis(benzyloxy)phosphoryl)oxy)phenyl)acetic acid. MS: (ES) m/zcalculated for C₂₂H₂₁O₆P [M+H]⁺413.1, found 413.1.

To a solution of iodomethyl4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indole-1-carboxylate(100 mg, 13 mmol) in DMF (0.5 mL) was added2-(4-((bis(benzyloxy)phosphoryl)oxy)phenyl)acetic acid (82 mg, 20 mmol)and triethylamine (0.03 mL, 0.20 mmol). The mixture was stirred at roomtemperature for 16 h then concentrated. The residue was purified bysilica gel column chromatography (0 to 100% EtOAc in hexanes) to provide(2-(4-((bis(benzyloxy)phosphoryl)oxy)phenyl)acetoxy)methyl4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indole-1-carboxylate.

Step b: To a solution of(2-(4-((bis(benzyloxy)phosphoryl)oxy)phenyl)acetoxy)methyl4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indole-1-carboxylate(66 mg, 0.06 mmol) in MeOH (1 mL) was added 10% Pd/C (7 mg, 0.006 mmol).The mixture was stirred under a H2 balloon for 1 h, then filteredthrough Celite, concentrated and purified by HPLC (MeCN/H₂O, with 0.1%TFA) to yield (2-(4-(phosphonooxy)phenyl)acetoxy)methyl4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indole-1-carboxylate.¹H NMR (400 MHz, CDCl₃) δ 8.47 (s, 2H), 7.38 (d, J=3.8 Hz, 1H),7.22-7.26 (m, 2H), 7.10 (d, J=7.7 Hz, 2H), 7.01-7.06 (m, 4H), 6.57 (d,J=12.1 Hz, 1H), 6.45 (d, J=3.8 Hz, 1H), 5.97 (s, 2H), 5.02 (br s, 2H),4.77 (s, 2H), 4.36 (br s, 2H), 3.95 (s, 3H), 3.60 (s, 2H), 3.07 (br s,2H), 2.05-2.35 (m, 4H), 0.99 (br s, 6H). MS: (ES) m/z calculated forC₄₀H₃₇F₄N₆O₉P [M+H]⁺ 853.2, found 853.0.

Example 13: Synthesis of(4-phosphonooxy-3-(trifluoromethyl)phenyl)methylN-((4-(5-((2,4-bis(trifluoromethyl)phenyl)methyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-4H-pyrrolo[3,4-c]pyrazol-3-yl)-2,5-difluorophenyl)carbamoyl)carbamate

Step a: To a solution of 4-hydroxy-3-(trifluoromethyl)benzaldehyde (1 g,0.53 mmol) in dichloromethane (10 mL) was added triethylamine (1.1 mL,0.79 mmol) followed by diethylchlorophosphate (0.84 mL, 0.58 mmol). Themixture was stirred at room temperature for 1 h then concentrated invacuo. The residue was purified by silica gel column chromatography (0to 100% EtOAc in hexanes) to afford diethyl(4-formyl-2-(trifluoromethyl)phenyl)phosphate. MS: (ES) m/z calculatedfor C₁₂H₁₄F₃O₅P [M+H]⁺ 327.1, found 327.0.

To a solution of diethyl (4-formyl-2-(trifluoromethyl)phenyl)phosphate(1.43 g, 4.4 mmol) in THF (4.5 mL) at −78° C. was added NaBH₄ (0.49 g,13.2 mmol). The reaction mixture was warmed to room temperature andstirred for 16 h. Upon completion, the reaction was quenched with H₂O.The organic and aqueous layers were separated, and the aqueous layer wasextract with EtOAc. The organic layers were combined, dried with sodiumsulfate, filtered and concentrated in vacuo. The residue was purified bysilica gel column chromatography (85 to 100% EtOAc in hexanes) toproduce diethyl (4-(hydroxymethyl)-2-(trifluoromethyl)phenyl)phosphate.MS: (ES) m/z calculated for C₁₂H₁₆F₃O₅P [M+H]⁺ 329.1, found 329.1.

To a solution of diethyl(4-(hydroxymethyl)-2-(trifluoromethyl)phenyl)phosphate (0.6 g, 1.8 mmol)in THF (4.4 mL) at 0° C. was added diisopropylethylamine (0.39 mL, 2.2mmol) and triphosgene (0.27 mL, 0.9 mmol). After stirring at 0° C. for 1h, NH₄OH (0.8 mL, 21 mmol) was added. The mixture was stirred at roomtemperature for 1 h then concentrated in vacuo and the residue waspurified by silica gel column chromatography (0 to 100% EtOAc inhexanes) to provide 4-((diethoxyphosphoryloxy)-3-(trifluoromethyl)benzylcarbamate. MS: (ES) m/z calculated for C₁₃H₁₇F₃NO₆P [M+H]⁺ 372.1, found372.0.

To a solution of 4-((diethoxyphosphoryl)oxy)-3-(trifluoromethyl)benzylcarbamate (240 mg, 0.65 mmol) in dichloromethane (2 mL) at 0° C. wasadded oxalyl chloride (0.09 mL, 1.0 mmol). The mixture was heated at 40°C. for 16 h then concentrated in vacuo. The residue was dissolved in 2mL of THF and added to a solution of4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-2,5-difluoroaniline(200 mg, 0.32 mmol) in THF (4 mL). The mixture was stirred at roomtemperature for 5 h then concentrated in vacuo. The residue was purifiedby silica gel column chromatography (0 to 100% EtOAc in hexanes) to give(4-diethoxyphosphoryloxy-3-(trifluoromethyl)phenyl)methylN-((4-(5-((2,4-bis(trifluoromethyl)phenyl)methyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-4H-pyrrolo[3,4-c]pyrazol-3-yl)-2,5-difluorophenyl)carbamoyl)carbamate.

Step b: To a solution of(4-diethoxyphosphoryloxy-3-(trifluoromethyl)phenyl)methylN-(4-(5-((2,4-bis(trifluoromethyl)phenyl)methyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-4H-pyrrolo[3,4-c]pyrazol-3-yl)-2,5-difluorophenyl)carbamoyl)carbamate(176 mg, 0.17 mmol) in dichloromethane (1.7 mL) was added dropwise TMSBr(0.29 mL, 2 mmol). The mixture was stirred at room temperature for 16 hthen concentrated in vacuo. The residue was purified on HPLC (MeCN/H₂O,with 0.1% TFA) to yield (4-phosphonooxy-3-(trifluoromethyl)phenyl)methylN-((4-(5-((2,4-bis(trifluoromethyl)phenyl)methyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-4H-pyrrolo[3,4-c]pyrazol-3-yl)-2,5-difluorophenyl)carbamoyl)carbamate.¹H NMR (400 MHz, DMSO-d₆) δ: 10.80 (s, 1H), 10.11 (s, 1H), 8.15 (s, 1H),7.90-8.15 (m, 3H), 7.73 (bs, 1H), 7.63-7.69 (m, 1H), 7.54-7.61 (m, 1H),7.35-7.42 (m, 1H), 7.18-7.24 (m, 2H), 6.49-6.58 (m, 1H), 5.19 (s, 2H),4.13 (s, 2H), 3.65 (s, 2H), 2.07-2.23 (m, 4H), 1.30-1.40 (m, 6H),0.88-1.03 (m, 6H). MS: (ES) m/z calculated for C₄₂H₃₇F₁₁N₅O₇P [M+H]⁺964.2, found 964.0.

Example 14: Synthesis of (3-nitro-4-phosphonooxyphenyl)methylN-((4-(5-(2,4-bis(trifluoromethyl)phenyl)methyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-4H-pyrrolo[3,4-c]pyrazol-3-yl)-2,5-difluorophenyl)carbamoyl)carbamate

Step a: To a solution of 4-hydroxy-3-nitrobenzaldehyde (1 g, 6.0 mmol)in dichloromethane (6 mL) was added Et₃N (1.25 mL, 9.0 mmol) anddiethylchlorophosphate (0.95 mL, 6.6 mmol). The mixture was stirred atroom temperature for 16 h then quenched with H₂O. The organic andaqueous layers were separated, and the aqueous layer was extracted withEtOAc. The organic layers were combined, dried with sodium sulfate,filtered and concentrated in vacuo. The residue was purified by silicagel column chromatography (0 to 100% EtOAc in hexanes) to afford diethyl(4-formyl-2-nitrophenyl)phosphate. MS: (ES) m/z calculated forC₁₁H₁₄NO₇P [M+H]⁺ 304.1, found 304.0.

To a solution of diethyl (4-formyl-2-nitrophenyl)phosphate (1.36 g, 4.5mmol) in THF (4.5 mL) at −78° C. was added NaBH₄ (500 mg, 13.5 mmol).After stirring at −78° C. for 1 h the reaction was quenched with H₂O.The organic and aqueous layers were separated, and the aqueous layer wasextracted with EtOAc. The organic layers were combined, dried withsodium sulfate, filtered, and concentrated. The residue was purified bysilica gel column chromatography (0 to 100% EtOAc in hexanes) to providediethyl (4-(hydroxymethyl)-2-nitrophenyl)phosphate. MS: (ES) m/zcalculated for C₁₁H₁₆NO₇P [M+H]⁺ 306.1, found 306.1.

To a solution of diethyl (4-(hydroxymethyl)-2-nitrophenyl)phosphate (200mg, 0.66 mmol) in THF (1.6 mL) at 0° C. was added diisopropylethylamine(0.14 mL, 0.80 mmol) and triphosgene (100 mg, 0.34 mmol). After stirringat 0° C. for 1 h, NH₄OH (0.32 mL, 8.2 mmol) was added. The mixture wasstirred at room temperature for 1 h then concentrated in vacuo and theresidue was purified by silica gel column chromatography (0 to 100%EtOAc in hexanes) to provide 4-((diethoxyphosphoryl)oxy)-3-nitrobenzylcarbamate. MS: (ES) m/z calculated for C₁₂H₁₇N₂O₈P [M+H]⁺ 349.1, found349.0.

To a solution of 4-((diethoxyphosphoryl)oxy)-3-(trifluoromethyl)benzylcarbamate (0.4 g, 1.2 mmol) in dichloromethane (11.5 mL) at 0° C. wasadded oxalyl chloride (0.15 mL, 1.8 mmol). The mixture was heated at 40°C. for 16 h then concentrated in vacuo. The residue was dissolved in THF(1 mL) and added to a solution of4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-2,5-difluoroaniline(200 mg, 0.32 mmol) in THF (5 mL). The mixture was stirred at roomtemperature for 3 h then concentrated in vacuo. The residue was purifiedby silica gel column chromatography (0 to 100% EtOAc in hexanes) to give(4-diethoxyphosphoryloxy-3-nitrophenyl)methylN-((4-(5-((2,4-bis(trifluoromethyl)phenyl)methyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-4H-pyrrolo[3,4-c]pyrazol-3-yl)-2,5-difluorophenyl)carbamoyl)carbamate.

Step b: To a solution of (4-diethoxyphosphoryloxy-3-nitrophenyl)methylN-((4-(5-((2,4-bis(trifluoromethyl)phenyl)methyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-4H-pyrrolo[3,4-c]pyrazol-3-yl)-2,5-difluorophenyl)carbamoyl)carbamate(100 mg, 0.10 mmol) in dichloromethane (1 mL) was added dropwise TMSBr(0.09 mL, 0.6 mmol). After stirring at room temperature for 3 h, anadditional amount of TMSBr (0.09 mL, 0.6 mmol) was added to the mixture.The mixture was stirred at room temperature for 16 h, concentrated invacuo and purified by HPLC (MeCN/H₂O, with 0.1% TFA) to yield(3-nitro-4-phosphonooxyphenyl)methylN-((4-(5-((2,4-bis(trifluoromethyl)phenyl)methyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-4H-pyrrolo[3,4-c]pyrazol-3-yl)-2,5-difluorophenyl)carbamoyl)carbamate.¹H NMR (400 MHz, CD₃OD) δ: 8.25 (d, J=8.0 Hz, 1H), 8.16 (s, 2H),8.01-8.12 (m, 1H), 7.82 (s, 1H), 7.54 (s, 2H), 7.46 (t, J=7.7 Hz, 1H),7.28 (d, J=7.8 Hz, 2H), 6.38 (dd, J=7.6, 11.2 Hz, 1H), 5.20 (s, 2H),4.81 (s, 2H), 4.66 (s, 2H), 2.25 (q, J=7.7 Hz, 4H), 1.92 (s, 6H), 1.05(t, J=7.7 Hz, 6H). MS: (ES) m/z calculated for C₄₁H₃₇F₈N₆O₉P [M+H]⁺941.2, found 941.1

Example 15: Synthesis of2-(4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indole-1-carbonyl)-5-fluorobenzyldihydrogen phosphate

Step a: A vial containing 5-fluoroisobenzofuran-1(3H)-one (50 mg, 0.33mmol), boric acid (2 mg, 0.03 mmol), and triethylbenzylammonium chloride(6 mg, 0.03 mmol) was heated at 110° C. To the mixture was added thionylchloride (0.05 mL, 0.69 mmol). After stirring at 110° C. for 16 h, thecontents were concentrated to give 2-(chloromethyl)-4-fluorobenzoylchloride.

To a solution of2-(2,6-diethylphenyl)-3-(6-fluoro-7-methoxy-1H-indol-4-yl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine(46 mg, 0.08 mmol) in THF (0.5 mL) at −78° C. was added a 1 M solutionof LHMDS in THF (0.12 mL, 0.12 mmol). The mixture was stirred at −78° C.for 30 min, warmed to 0° C. and stirred for 15 min, then cooled backdown to −78° C. A solution of 2-(chloromethyl)-4-fluorobenzoyl chloride(0.33 mmol) in THF (0.5 mL) was added dropwise to the mixture. Afterstirring at room temperature for 16 h, the reaction was quenched withH₂O. The aqueous and organic layers were separated, and the aqueouslayer was extracted with EtOAc. The organic layers were combined, driedwith sodium sulfate, filtered and concentrated. The residue was purifiedby silica gel column chromatography (0 to 100% EtOAc in hexanes) toyield(2-(chloromethyl)-4-fluorophenyl)(4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indol-1-yl)methanone.MS: (ES) m/z calculated for C₃₈H₃₂ClF₅N₆O₂ [M+H]⁺ 735.2, found 735.1.

Step b: To a solution of(2-(chloromethyl)-4-fluorophenyl)(4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indol-1-yl)methanone(48 mg, 0.065 mmol) in acetone (1 mL) was added sodium iodide (32 mg,0.21 mmol). The mixture was heated at 70° C. for 1 h then concentratedin vacuo. The residue was purified by silica gel column chromatography(0 to 100% EtOAc in hexanes) to produce(4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indol-1-yl)(4-fluoro-2-(iodomethyl)phenyl)methanone.MS: (ES) m/z calculated for C₃₈H₃₂F₅IN₆O₂ [M+H]⁺ 827.2, found 827.0.

Step c: To a solution of(4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indol-1-yl)(4-fluoro-2-(iodomethyl)phenyl)methanone(26 mg, 0.031 mmol) in toluene (1 mL) was added silver dibenzylphosphate(24 mg, 0.062 mmol). The mixture was heated at 110° C. for 16 h thenconcentrated in vacuo. The residue was purified by silica gel columnchromatography (0 to 100% EtOAc in hexanes) to provide dibenzyl(2-(4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indole-1-carbonyl)-5-fluorobenzyl)phosphate.

Step d: To a solution of dibenzyl(2-(4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indole-1-carbonyl)-5-fluorobenzyl)phosphate (17 mg, 0.017 mmol) in MeOH (1 mL) was added 10% Pd/C (2 mg).The mixture was stirred under a H2 balloon for 1 h, then filteredthrough Celite, concentrated and purified by HPLC (MeCN/H₂O, with 0.1%TFA) to yield2-(4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indole-1-carbonyl)-5-fluorobenzyldihydrogen phosphate. ¹H NMR (400 MHz, CD₃OD) δ 8.58 (s, 2H), 7.60 (d,J=10.0 Hz, 1H), 7.49 (br s, 2H), 7.33 (t, J=7.6 Hz, 1H), 7.11-7.24 (m,3H), 6.65 (s, 1H), 6.59 (d, J=13.0 Hz, 1H), 5.35 (d, J=7.3 Hz, 2H), 4.87(s, 2H), 4.38 (s, 2H), 3.75 (s, 3H), 2.98 (s, 2H), 2.25 (br s, 4H), 1.02(br s, 6H). MS: (ES) m/z calculated for C₃₈H₃₄F₅N₆O₆P [M+H]⁺ 797.2,found 797.1.

Example 16: Synthesis of2-(4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indole-1-carbonyl)benzyldimethylglycinate

Step a: To a solution of2-(2,6-diethylphenyl)-3-(6-fluoro-7-methoxy-1H-indol-4-yl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine(500 mg, 0.9 mmol) in THF (8.8 mL) at −78° C. was added a 1 M solutionof LHMDS in THF (0.98 mL, 0.98 mmol). After stirring at −78° C. for 30min, 2-(chloromethyl)benzoyl chloride (0.25 mL, 1.78 mmol) was added tothe mixture. After stirring at room temperature for 16 h, the reactionwas quenched with H₂O. The aqueous and organic layers were separated,and the aqueous layer was extracted with EtOAc. The organic layers werecombined, dried with sodium sulfate, filtered and concentrated. Theresidue was purified by silica gel column chromatography (0 to 100%EtOAc in hexanes) to yield(2-(chloromethyl)phenyl)(4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indol-1-yl)methanone.MS: (ES) m/z calculated for C₃₈H₃₃ClF₄N₆O₂ [M+H]⁺ 717.2, found 717.0.

Step b: To a solution of(2-(chloromethyl)phenyl)(4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indol-1-yl)methanone(156 mg, 0.22 mmol) in acetone (2.2 mL) was added sodium iodide (129 mg,0.9 mmol). After heating at 70° C. for 1 h, the reaction was quenchedwith H₂O. The aqueous and organic layers were separated, and the aqueouslayer was extracted with EtOAc. The organic layers were combined, driedwith sodium sulfate, filtered and concentrated.

The residue was purified by silica gel column chromatography (0 to 100%EtOAc in hexanes) to produce(4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indol-1-yl)(2-(iodomethyl)phenyl)methanone.

Step c: To a solution of(4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indol-1-yl)(2-(iodomethyl)phenyl)methanone(76 mg, 0.094 mmol) in DMF (1 mL) at 0° C. was added Cs₂CO₃ (31 mg, 0.1mmol) and dimethylglycine (10 mg, 0.1 mmol). After stirring at roomtemperature for 16 h, the reaction was quenched with H₂O. The aqueousand organic layers were separated, and the aqueous layer was extractedwith EtOAc. The organic layers were combined, dried with sodium sulfate,filtered and concentrated. The residue was purified by HPLC (MeCN/H₂O,with 0.1% TFA) to provide2-(4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indole-1-carbonyl)benzyldimethylglycinate. ¹H NMR (400 MHz, CDCl₃) δ 8.54 (s, 2H), 7.65-7.81 (m,4H), 7.31 (t, J=7.7 Hz, 1H), 7.22 (d, J=3.7 Hz, 1H), 7.11 (br s, 2H),6.64 (d, J=12.7 Hz, 1H), 6.52 (d, J=3.7 Hz, 1H), 5.08 (s, 2H), 4.76 (s,2H), 4.37 (s, 2H), 4.14 (s, 2H), 3.85 (s, 3H), 3.32 (s, 6H), 3.09 (t,J=5.9 Hz, 2H), 2.08 (br s, 4H), 1.04 (br s, 6H). MS: (ES) m/z calculatedfor C₄₂H₄₁F₄N₇O₄ [M+H]⁺ 784.3, found 784.2.

Example 17: Synthesis of 3-chloro-4-(phosphonooxy)benzyl4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indole-1-carboxylate

Step a: To a flask containing 3-chloro-4-hydroxybenzoic acid (5 g, 29mmol) in MeOH (100 mL) was added dropwise thionyl chloride (7.4 mL, 102mmol). The mixture was heated at 60° C. for 1 h then concentrated invacuo. The crude residue was dissolved in THF (100 mL). To the solutionwas added LiAlH₄ (4.4 g, 110 mmol). After heating at 65° C. for 1 h, thereaction was quenched with 1 N HCl. The aqueous and organic layers wereseparated, and the aqueous layer was extracted with EtOAc. The organiclayers were combined, dried with sodium sulfate, filtered andconcentrated. The residue was purified by silica gel columnchromatography (0 to 100% EtOAc in hexanes) to afford2-chloro-4-(hydroxymethyl)phenol.

To a solution of 2-chloro-4-(hydroxymethyl)phenol (2 g, 12.7 mmol) indioxane (25 mL) was added DDQ (2.87 g, 12.7 mmol). The mixture wasstirred at room temperature for 4 h then filtered. The filtrate waswashed with H₂O, then dried with sodium sulfate, filtered andconcentrated. The residue was purified by silica gel columnchromatography (0 to 100% EtOAc in hexanes) to yield3-chloro-4-hydroxybenzaldehyde. MS: (ES) m/z calculated for C₇H₅ClO₂[M+H]⁺ 157.0, found 157.0.

To a flask containing 3-chloro-4-hydroxybenzaldehyde (1.4 g, 9.0 mmol)in THF (14.6 mL) was added dropwise a 1.0 M solution of tBuOK in THF(9.5 mL, 9.5 mmol) and tetrabenzyldiphosphate (4.8 g, 8.9 mmol). Themixture was heated at 70° C. for 2 h. Upon completion, hexanes was addedand the contents were filtered. The filtrate was concentrated and theresultant residue was purified by silica gel column chromatography (0 to100% EtOAc in hexanes) to afford dibenzyl(2-chloro-4-formylphenyl)phosphate. MS: (ES) m/z calculated forC₂₁H₁₈ClO₅P [M+H]⁺ 417.1, found 417.0.

To a solution of dibenzyl (2-chloro-4-formylphenyl)phosphate (2.75 g,6.6 mmol) in THF (6.6 mL) at −78° C. was added NaBH₄ (0.73 g, 19.7mmol). After stirring at −78° C. for 1 h, the reaction was quenched withH₂O. The organic and aqueous layers were separated, and the aqueouslayer was extracted with EtOAc. The organic layers were combined, driedwith sodium sulfate, filtered and concentrated in vacuo. The resultantresidue was purified by silica gel column chromatography (0 to 100%EtOAc in hexanes) to produce dibenzyl(2-chloro-4-(hydroxymethyl)phenyl)phosphate. MS: (ES) m/z calculated forC₂₁H₂₀ClO₅P [M+H]⁺ 419.1, found 419.0.

To a solution of dibenzyl (2-chloro-4-(hydroxymethyl)phenyl)phosphate(250 mg, 0.6 mmol) in THF (3 mL) at 0° C. was addeddiisopropylethylamine (0.12 mL, 0.69 mmol) and triphosgene (92 mg, 0.3mmol). After stirring at 0° C. for 1 h, the reaction was quenched withH₂O. The organic and aqueous layers were separated and the aqueous layerwas extracted with EtOAc. The organic layers were combined, dried withsodium sulfate, filtered and concentrated to afford the crudechloroformate.

To a solution of4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indole(187 mg, 0.30 mmol) in THF (1.5 mL) at 0° C. was added NaH (24 mg, 0.60mmol). After stirring at 0° C. for 30 min, a solution of the crudechloroformate (prepared above) in THF (1.5 mL), was added to themixture. After stirring at 0° C. for 1 h, the reaction was quenched withH₂O. The organic and aqueous layers were separated and the aqueous layerwas extracted with EtOAc. The organic layers were combined, dried withsodium sulfate, filtered and concentrated in vacuo. The residue waspurified by silica gel column chromatography (0 to 100% EtOAc inhexanes) to produce 4-((bis(benzyloxy)phosphoryl)oxy)-3-chlorobenzyl4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indole-1-carboxylate.

Step b: To a solution of4-((bis(benzyloxy)phosphoryl)oxy)-3-chlorobenzyl4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indole-1-carboxylate(298 mg, 0.28 mmol) in MeOH (4 mL) was added 10% Pd/C (30 mg, 0.03mmol). The mixture was stirred under a H2 balloon for 1 h, then filteredthrough Celite, concentrated and purified by HPLC (MeCN/H₂O, with 0.1%TFA) to yield 3-chloro-4-(phosphonooxy)benzyl4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indole-1-carboxylate.¹H NMR (400 MHz, CD₃OD) δ 8.12 (s, 1H), 8.04-8.12 (m, 2H), 7.83 (s, 1H),7.55 (s, 1H), 7.51 (d, J=8.4 Hz, 1H), 7.33-7.37 (m, 2H), 7.17 (d, J=7.9Hz, 2H), 6.82 (dd, J=10.2, 10.2 Hz, 1H), 6.67 (br s, 2H), 5.36 (s, 2H),4.77 (s, 2H), 4.50 (s, 2H), 2.16-2.29 (m, 4H), 1.93 (br s, 6H), 0.99 (brs, 6H). MS: (ES) m/z calculated for C₄₂H₃₇ClF₇N₄O₆P [M+H]⁺ 893.2, found893.1.

Example 18: Synthesis of 3-fluoro-4-(phosphonooxy)benzyl4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indole-1-carboxylate

Step a: To a flask containing 3-fluoro-4-hydroxybenzaldehyde (1 g, 7.1mmol) in THF (32 mL) was added dropwise a 1.0 M solution of tBuOK in THF(7.6 mL, 7.6 mmol) and tetrabenzyldiphosphate (4.0 g, 7.4 mmol). Themixture was heated at 70° C. for 1 h. Upon completion, hexanes was addedand the contents were filtered. The filtrate was concentrated and theresidue was purified by silica gel column chromatography (0 to 100%EtOAc in hexanes) to afford dibenzyl (2-fluoro-4-formylphenyl)phosphate. MS: (ES) m/z calculated for C₂₁H₁₈FO₅P [M+H]⁺ 401.1, found401.1.

To a solution of dibenzyl (2-fluoro-4-formylphenyl) phosphate (2.68 g,6.7 mmol) in THF (6.7 mL) at −78° C. was added NaBH₄ (0.76 g, 20.5mmol). After stirring at −78° C. for 1 h, the reaction was quenched withH₂O. The organic and aqueous layers were separated, and the aqueouslayer was extract with EtOAc. The organic layers were combined, driedwith sodium sulfate, filtered and concentrated in vacuo. The residue waspurified by silica gel column chromatography (0 to 100% EtOAc inhexanes) to produce dibenzyl (2-fluoro-4-(hydroxymethyl)phenyl)phosphate. MS: (ES) m/z calculated for C₂₁H₂₀FO₅P [M+H]⁺ 403.1, found403.0.

To a solution of dibenzyl (2-fluoro-4-(hydroxymethyl)phenyl)phosphate(250 mg, 0.62 mmol) in THF (3 mL) at 0° C. was addeddiisopropylethylamine (0.12 mL, 0.69 mmol) and triphosgene (92 mg, 0.3mmol). After stirring at room temperature for 30 min, the reaction wasquenched with H₂O. The organic and aqueous layers were separated, andthe aqueous layer was extracted with EtOAc. The organic layers werecombined, dried with sodium sulfate, filtered and concentrated to affordthe crude chloroformate.

To a solution of4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indole(195 mg, 0.31 mmol) in THF (1.5 mL) at 0° C. was added NaH (24 mg, 0.60mmol). After stirring at room temperature for 30 min, a solution of thecrude chloroformate (prepared above) in THF (1.5 mL), was added to themixture. After stirring at room temperature for 16 h, the reaction wasquenched with H₂O. The organic and aqueous layers were separated, andthe aqueous layer was extracted with EtOAc. The organic layers werecombined, dried with sodium sulfate, filtered and concentrated in vacuo.The residue was purified by silica gel column chromatography (0 to 100%EtOAc in hexanes) to produce4-((bis(benzyloxy)phosphoryl)oxy)-3-fluorobenzyl4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indole-1-carboxylate.

Step b: To a solution of4-((bis(benzyloxy)phosphoryl)oxy)-3-fluorobenzyl4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indole-1-carboxylate(307 mg, 0.29 mmol) in EtOAc (1.5 mL) was added 10% Pd/C (30 mg, 0.03mmol). The mixture was stirred under a H2 balloon for 3 h, then filteredthrough Celite, concentrated and purified by HPLC (MeCN/H₂O, with 0.1%TFA) to yield 3-fluoro-4-(phosphonooxy)benzyl4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indole-1-carboxylate.¹H NMR (400 MHz, CD₃OD) δ: 8.13 (s, 1H), 8.05-8.11 (m, 2H), 7.83 (m,1H), 7.44 (dd, J=8.4, 8.4 Hz, 1H), 7.30-7.37 (m, 2H), 7.23 (d, J=8.4 Hz,1H), 7.17 (d, J=7.8 Hz, 2H), 6.83 (dd, J=10.4, 10.4 Hz, 1H), 6.67 (br s,2H), 5.38 (s, 2H), 4.80 (s, 2H), 4.54 (s, 2H), 2.15-2.29 (m, 4H), 1.96(br s, 6H), 0.99 (br s, 6H). MS: (ES) m/z calculated for C₄₂H₃₇F₈N₄O₆P[M+H]⁺ 877.2, found 877.1.

Example 19: Synthesis of 2-((phosphonooxy)methyl)phenyl4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indole-1-carboxylate

Step a: To a flask containing 2-hydroxybenzaldehyde (10 g, 82 mmol) inDMF (82 mL) was added dropwise imidazole (6.1 g, 90 mmol) and TBDMSC1(13.6 g, 90 mmol). After stirring at room temperature for 3 h, thereaction was quenched with H₂O. The mixture was extracted with EtOAc.The combined organic layers were dried with sodium sulfate, filtered andconcentrated. The residue was purified by silica gel columnchromatography (0-100% EtOAc in hexanes) to afford2-((tert-butyldimethylsilyl)oxy)benzaldehyde. MS: (ES) m/z calculatedfor C₁₃H₂₀O₂Si [M+H]⁺ 237.1, found 237.1.

To a solution of 2-((tert-butyldimethylsilyl)oxy)benzaldehyde (16.4 g,69 mmol) in MeOH (126 mL) was added NaBH₄ (2.55 g, 67.4 mmol). Afterstirring at room temperature for 2 h, the reaction was quenched withH₂O. The mixture was concentrated in vacuo then extracted with hexanes.The organic layers were combined, dried with sodium sulfate, filteredand concentrated in vacuo. The residue was purified by silica gel columnchromatography (0 to 10% EtOAc in hexanes) to produce(2-((tert-butyldimethylsilyl)oxy)phenyl)methanol.

To a flask containing (2-((tert-butyldimethylsilyl)oxy)phenyl)methanol(1 g, 4.2 mmol) in THF (42 mL) was added dropwise a 1.0 M solution oftBuOK in THF (4.6 mL, 4.6 mmol) and tetrabenzyldiphosphate (2.5 g, 4.6mmol). The mixture was heated at 60° C. for 1 h. Upon completion,hexanes was added and the contents were filtered. The filtrate wasconcentrated and the residue was used without further purification.

To a solution of the crude residue dissolved in MeCN (42 mL) was addeddropwise HF-pyridine (4.2 mL). After stirring at room temperature for 1h the mixture was concentrated in vacuo. The residue was purified bysilica gel column chromatography (0 to 100% EtOAc in hexanes) to yielddibenzyl (2-hydroxybenzyl)phosphate. MS: (ES) m/z calculated forC₂₁H₂₁O₅P [M+H]⁺ 385.1, found 385.0.

To a solution of dibenzyl (2-hydroxybenzyl)phosphate (366 mg, 0.95 mmol)in THF (4.8 mL) was added diisopropylethylamine (0.18 mL, 1.0 mmol) andtriphosgene (139 mg, 0.47 mmol). After stirring at room temperature for30 min, the reaction was quenched with H₂O. The organic and aqueouslayers were separated and the aqueous layer was extracted with EtOAc.The organic layers were combined, dried with sodium sulfate, filteredand concentrated.

To a solution of4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indole(300 mg, 0.48 mmol) in THF (4.8 mL) was added NaH (37 mg, 0.97 mmol).After stirring at room temperature for 20 min, a solution of the crudechloroformate (prepared above) in 1 mL of THF, was added to the mixture.After stirring at room temperature for 16 h, the reaction was quenchedwith H₂O. The organic and aqueous layers were separated, and the aqueouslayer was extracted with EtOAc. The organic layers were combined, driedwith sodium sulfate, filtered and concentrated in vacuo. The residue waspurified by silica gel column chromatography (0 to 100% EtOAc inhexanes) to produce 2-(((bis(benzyloxy)phosphoryl)oxy)methyl)phenyl4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indole-1-carboxylate.

Step b: To a solution 2-(((bis(benzyloxy)phosphoryl)oxy)methyl)phenyl4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indole-1-carboxylate(500 mg, 0.48 mmol) in EtOAc (2.4 mL) was added 10% Pd/C (51 mg). Themixture was stirred under a H2 balloon for 2 h, then filtered throughCelite, concentrated and purified by HPLC (MeCN/H₂O, with 0.1% TFA) toyield 2-((phosphonooxy)methyl)phenyl4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indole-1-carboxylate.¹H NMR (400 MHz, DMSO-d₆) δ 8.12 (d, J=8.1 Hz, 1H), 7.94-8.06 (m, 2H),7.85 (s, 1H), 7.51 (d, J=7.6 Hz, 1H), 7.35-7.39 (m, 1H), 7.28-7.33 (m,2H), 7.07-7.20 (m, 3H), 6.90-6.95 (m, 1H), 6.60 (s, 1H), 6.56 (dd,J=8.4, 3.7 Hz, 1H), 5.42 (s, 2H), 4.15 (br s, 2H), 3.59 (br s, 2H), 2.16(q, J=7.8 Hz, 4H), 1.48 (br s, 6H), 0.90 (t, J=7.5 Hz, 6H). MS: (ES) m/zcalculated for C₄₂H₃₈F₇N₄O₆P [M+H]⁺ 859.2, found 859.2.

Example 20: Synthesis of2-(4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indole-1-carbonyl)benzyldihydrogen phosphate

Step a: To a solution of4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indole(500 mg, 0.80 mmol) in THF (8 mL) at −78° C. was added a 0.5 M solutionof KHMDS in THF (2.6 mL, 1.3 mmol). After stirring at −78° C. for 30min, 2-(chloromethyl)benzoyl chloride (0.28 mL, 1.9 mmol) was added tothe mixture. After stirring at room temperature for 16 h, the reactionwas diluted with EtOAc and washed with satuated aqueous NaHCO₃ solution.The aqueous and organic layers were separated, and the aqueous layer wasextracted with EtOAc. The organic layers were combined, dried withsodium sulfate, filtered and concentrated. The residue was purified bysilica gel column chromatography (0 to 100% EtOAc in hexanes) to yield(4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indol-1-yl)(2-(chloromethyl)phenyl)methanone.MS: (ES) m/z calculated for C₄₂H₃₆ClF₇N₄O [M+H]⁺ 781.3, found 781.0.

Step b: To a solution of(4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indol-1-yl)(2-(chloromethyl)phenyl)methanone(194 mg, 0.25 mmol) in acetone (3.1 mL) was added sodium iodide (149 mg,0.99 mmol). After heating at 70° C. for 2 h, the reaction was dilutedwith EtOAc and washed with H₂O. The aqueous and organic layers wereseparated, and the aqueous layer was extracted with EtOAc. The organiclayers were combined, dried with sodium sulfate, filtered andconcentrated to produce(4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indol-1-yl)(2-(iodomethyl)phenyl)methanone,which was used in the subsequent step without further purification.

Step c: To a solution of crude(4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indol-1-yl)(2-(iodomethyl)phenyl)methanone(0.25 mmol) in toluene (1 mL) was added silver dibenzylphosphate (190mg, 0.49 mmol). After heating the mixture at 110° C. for 3 h, themixture was filtered through Celite. The filtrate was concentrated andthe residue was purified by silica gel column chromatography (0 to 100%EtOAc in hexanes) to provide dibenzyl(2-(4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indole-1-carbonyl)benzyl)phosphate.

Step d: To a solution of dibenzyl(2-(4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indole-1-carbonyl)benzyl)phosphate(96 mg) in EtOAc (1 mL) was added 10% Pd/C (10 mg, 0.009 mmol). Themixture was stirred under a H2 balloon for 4 h, then filtered throughCelite, concentrated and purified by HPLC (MeCN/H₂O, with 0.1% TFA) toyield2-(4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indole-1-carbonyl)benzyldihydrogen phosphate. ¹H NMR (400 MHz, CD₃OD) δ: 8.12 (s, 1H), 8.09 (brs, 2H), 7.74 (d, J=7.7 Hz, 1H), 7.67 (ddd, J=1.4, 7.3, 7.3 Hz, 1H), 7.57(dd, J=1.4, 7.7 Hz, 1H), 7.49 (ddd, J=1.4, 7.2, 7.2 Hz, 1H), 7.40 (d,J=3.7 Hz, 1H), 7.36 (d, J=7.7 Hz, 1H), 7.20 (d, J=7.7 Hz, 1H), 6.84 (dd,J=8.3, 11.3 Hz, 1H), 6.72 (dd, J=3.8, 8.4 Hz, 1H), 6.67 (dd, J=1.8, 3.8Hz, 1H), 5.19 (d, J=7.4 Hz, 2H), 4.75 (s, 2H), 4.55 (s, 2H), 2.26 (q,J=7.5 Hz, 4H), 1.93 (s, 6H), 1.03 (t, J=7.5 Hz, 6H). MS: (ES) m/zcalculated for C₄₂H₃₈F₇N₄O₅P [M+H]⁺ 843.3, found 843.2.

Example 21: Synthesis of ((4-(piperazin-1-ylmethyl)benzoyl)oxy)methyl4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indole-1-carboxylate

Step a: A mixture of iodomethyl4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indole-1-carboxylate(840 mg, 1.12 mmol), 4-formylbenzoic acid (252 mg, 1.68 mmol) anddiisopropylethylamine (0.74 mL, 4.48 mmol) in dichloromethane (20 mL)was heated to 50° C. for 3 h. The mixture was cooled to roomtemperature, poured into saturated aqueous NaHCO₃ solution and extractedwith dichloromethane. The organic layer was separated, dried overNa₂SO₄, concentrated under reduced pressure and purified by silica gelflash chromatography (0 to 60% EtOAc in hexanes) to afford((4-formylbenzoyl)oxy)methyl4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indole-1-carboxylate.MS: (ES) m/z calculated for C₄₀H₃₅F₄N₆O₆[M+H]⁺ 771.2, found 771.2.

Step b: To a 200 mL flask containing piperazine (1.0 g, 11.6 mmol) indichloromethane (25 mL) at 0° C. was added sequentially acetic acid (40mL), NaBH(OAc)₃ (1.5 g, 7.0 mmol) and ((4-formylbenzoyl)oxy)methyl4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indole-1-carboxylate(0.5 g, 0.65 mmol). The mixture was allowed to warm to room temperatureand stirred overnight. The mixture was cooled to 0° C. and charged with2 M HCl solution in ether (20 mL, 40 mmol). The mixture was purified bysilica gel flash chromatography (0 to 100% EtOAc in hexanes followed by0 to 60% MeOH in CH₂Cl₂). The pure fractions were combined, cooled to 0°C., charged with 2 M HCl solution in ether (10 mL, 20 mmol) andconcentrated under reduced pressure to yield the HCl salt of of((4-(piperazin-1-ylmethyl)benzoyl)oxy)methyl4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indole-1-carboxylate.¹H NMR (400 MHz, CD₃OD) δ 8.58 (s, 2H), 8.21 (d, J=8.4 Hz, 2H), 7.80 (d,J=3.6 Hz, 1H), 7.75 (d, J=8.0 Hz, 2H), 7.33 (t, J=7.8 Hz, 1H), 7.16 (brs, 2H), 6.59-6.66 (m, 2H), 6.30 (s, 2H), 4.32-4.50 (m, 4H), 3.96 (d,J=1.2 Hz, 3H), 3.40-3.60 (m, 9H), 3.28-3.34 (m, 3H), 2.98 (dd, J=5.8,5.8 Hz, 2H), 2.25 (br s, 4H), 1.00 (br s, 6H); MS (free form): (ES) m/zcalculated for C₄₄H₄₅F₄N₈O₅ [M+H]⁺ 841.3, found 841.7.

Example 22: Synthesis of ((4-((phosphonooxy)methyl)benzoyl)oxy)methyl4-(5-(2,4-bis(trifluoromethyl)-benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indole-1-carboxylate

Step a: To a solution of4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indole(3.0 g, 4.76 mmol) in THF (30 mL) at −78° C. was added 1 M LiHMDSsolution in toluene (7.61 mL, 7.61 mmol) dropwise. The mixture wasstirred at the same temperature for an additional 15 min. Chloromethylcarbonochloridate (0.83 mL, 9.52 mmol) was added to the mixture. Theresulting mixture was allowed to warm to room temperature and stirredfor 0.5 h. The mixture was quenched with saturated aqueous NH₄Clsolution and extracted with EtOAc. The organic layer was separated,washed with saturated aqueous NaHCO₃ solution, dried over Na₂SO₄,concentrated under reduced pressure and purified by silica gel flashchromatography (0 to 40% EtOAc in hexanes) to afford chloromethyl4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indole-1-carboxylate.MS: (ES) m/z calculated for C₃₆H₃₃ClF₇N₄O₂[M+H]⁺ 721.1, found 721.0.

Step b: A mixture of chloromethyl4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indole-1-carboxylate.(2.5 g, 3.46 mmol) and NaI (6.0 g, 40.0 mmol) in acetone (50 mL) washeated to 45° C. for 7 h. The mixture was cooled to room temperature,poured into saturated aqueous NaHCO₃solution and extracted with EtOAc.The organic layer was separated, dried over Na₂SO₄, concentrated underreduced pressure and purified by silica gel flash chromatography (0 to40% EtOAc in hexanes) to afford iodomethyl4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indole-1-carboxylate.MS: (ES) m/z calculated for C₃₆H₃₃F₇IN₄O₂[M+H]⁺ 813.2, found 813.2.

Step c: A mixture of iodomethyl4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indole-1-carboxylate(156 mg, 0.19 mmol) and((4-(((bis(benzyloxy)phosphoryl)oxy)methyl)benzoyl)oxy)silver (100 mg,0.19 mmol) in toluene (10 mL) was heated to 110° C. for 1 h. It wascooled to room temperature, poured into saturated aqueous NaHCO₃solution and extracted with EtOAc. The organic layer was separated,dried over Na₂SO₄, concentrated under reduced pressure and purified bysilica gel flash chromatography (0 to 60% EtOAc in hexanes followed by 0to 30% EtOAc in CH₂Cl₂) to afford((4-(((bis(benzyloxy)phosphoryl)oxy)methyl)-benzoyl)oxy)methyl4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indole-1-carboxylate.MS: (ES) m/z calculated for C₅₈H₅₃F₇N₄O₈P [M+H]⁺ 1097.3, only fragmentof parent MS observed.

Step d: A mixture of((4-(((bis(benzyloxy)phosphoryl)oxy)methyl)benzoyl)oxy)methyl4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indole-1-carboxylate(0.10 g, 0.09 mmol) TFA (1 mL), dichloromethane (1 mL) and water (1 mL)was heated to 45° C. for 6 h. It was cooled to room temperature,concentrated under reduced pressure and purified by HPLC (MeCN/H₂O, with0.1% TFA) to afford ((4-((phosphonooxy)methyl)benzoyl)oxy)methyl4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indole-1-carboxylateas TFA salt. ¹H NMR (400 MHz, CD₃OD) δ 8.01-8.13 (m, 6H), 7.85 (d, J=3.6Hz, 1H), 7.54 (d, J=8.4 Hz, 2H), 7.35 (dd, J=7.8, 7.8 Hz, 1H), 7.16 (d,J=8.0 Hz, 2H), 6.81-6.88 (m, 1H), 6.66-6.71 (m, 2H), 6.26 (s, 2H), 5.07(d, J=7.2 Hz, 2H), 4.70 (br s, 2H), 4.40 (br s, 2H), 3.30 (br s, 2H),2.16-2.30 (m, 4H), 1.88 (s, 6H), 1.00 (t, J=7.6 Hz, 6H); MS: (ES) m/zcalculated for C₄₄H₄₁F₇N₄O₈P [M+H]⁺917.3, found 917.1.

Example 23: Synthesis of ((4-(piperazin-1-ylmethyl)benzoyl)oxy)methyl4-(5-(2,4-bis(trifluoromethyl)-benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indole-1-carboxylate

Step a: A mixture of 4-formylbenzoic acid (0.5 g, 3.3 mmol) and LiOHmonohydrate (0.15 g, 3.7 mmol) in THF (7.5 mL), MeOH (1 mL) and water(0.5 mL) was stirred at room temperature for 15 minutes. To the mixturewas added AgNO₃ (0.65 g, 3.8 mmol). The mixture was stirred for anadditional 15 minutes and evaporated to dryness under reduced pressureto afford ((4-formylbenzoyl)oxy)silver.

A mixture of iodomethyl4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indole-1-carboxylate(0.30 g, 0.37 mmol) and the above ((4-formylbenzoyl)oxy)silver (0.14 g,0.55 mmol) in toluene (5 mL) was heated to 100° C. for 1 h. It wascooled to room temperature, poured into saturated aqueous NaHCO₃solution and extracted with EtOAc. The organic layer was separated,dried over Na₂SO₄, concentrated under reduced pressure and purified bysilica gel flash chromatography (0 to 60% EtOAc in hexanes) to afford((4-formylbenzoyl)oxy)methyl445-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indole-1-carboxylate.MS: (ES) m/z calculated for C₄₄H₃₈F₇N₄O₅ [M+H]⁺ 835.3, found 835.3.

Step c: To a vial containing piperazine (0.150 g, 1.74 mmol) indichloromethane (4 mL) at 0° C. was added acetic acid (3 mL), NaBH(OAc)₃(0.400 g, 1.88 mmol) and ((4-formylbenzoyl)oxy)methyl4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indole-1-carboxylate(0.060 g, 0.071 mmol) in sequence. The mixture was allowed to warm up toroom temperature and stirred overnight. The mixture was cooled to 0° C.and quenched 2 M HCl solution in ether (2 mL, 4 mmol). The mixture waspurified by silica gel flash chromatography (0 to 100% MeOH in CH₂Cl₂).The pure fractions were combined, cooled to 0° C., charged with 2 M HClsolution in ether (2 mL, 4 mmol) and concentrated under reduced pressureto yield HCl salt of ((4-(piperazin-1-ylmethyl)benzoyl)oxy)methyl4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indole-1-carboxylate.¹H NMR (400 MHz, CD₃OD) δ 8.04-8.26 (m, 6H), 7.74-7.90 (m, 3H), 7.35(dd, J=7.2, 7.2 Hz, 1H), 7.16 (d, J=7.2 Hz, 2H), 6.80-6.90 (m, 2H),6.66-6.74 (m, 1H), 6.27 (s, 2H), 4.80-5.00 (m, 2H), 4.58 (s, 2H), 4.36(br s, 1H), 3.63 (br s, 10H), 2.23 (br s, 4H), 2.03 (br s, 6H), 0.99 (t,J=6.4 Hz, 6H); MS: (ES) m/z calculated for C₄₈H₄₈F₇N₆O₄ [M+H]⁺ 905.3,found 905.3.

Example 24: Synthesis of ((4-((phosphonooxy)methyl)benzoyl)oxy)methyl4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indole-1-carboxylate

Step a: A mixture of iodomethyl4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indole-1-carboxylate(0.15 g, 0.20 mmol) and((4-(((bis(benzyloxy)phosphoryl)oxy)methyl)benzoyl)oxy)silver (0.11 g,0.21 mmol) in toluene (4 mL) was heated to 110° C. for 1 h. The mixturewas cooled to room temperature, poured into into saturated aqueousNaHCO₃ solution and extracted with EtOAc. The organic layer wasseparated, dried over Na₂SO₄, concentrated under reduced pressure andpurified by silica gel flash chromatography (0 to 40% EtOAc in CH₂Cl₂)to afford ((4-(((bis(benzyloxy)phosphoryl)oxy)methyl)benzoyl)oxy)methyl4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indole-1-carboxylate.MS: (ES) m/z calculated for C₅₄H₅₀F₄N₆O₉P [M+H]⁺ 1033.3, only fragmentof parent MS observed.

Step b: A mixture of((4-(((bis(benzyloxy)phosphoryl)oxy)methyl)benzoyl)oxy)methyl4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indole-1-carboxylate(0.08 g, 0.08 mmol), TFA (1 mL), dichloromethane (1 mL) and water (1 mL)was heated to 45° C. for 7 h. It was cooled to room temperature,concentrated under reduced pressure and purified by HPLC (MeCN/H₂O, with0.1% TFA) to afford ((4-((phosphonooxy)methyl)benzoyl)oxy)methyl4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indole-1-carboxylate.¹H NMR (400 MHz, CD₃OD) δ 8.55 (s, 2H), 8.10 (d, J=7.6 Hz, 2H), 7.78 (s,1H), 7.54 (d, J=8.0 Hz, 2H), 7.32 (dd, J=7.2 Hz, 1H), 7.15 (br s, 2H),6.57-6.64 (m, 2H), 6.28 (s, 2H), 5.08 (d, J=7.6 Hz, 2H), 4.81 (br s,2H), 4.36 (br s, 2H), 3.95 (s, 3H), 3.25-3.34 (m, 2H), 2.92-3.00 (m,2H), 2.20 (br s, 4H), 1.00 (br s, 6H); MS: (ES) m/z calculated forC₄₀H₃₈F₄N₆O₉P [M+H]⁺ 853.2, found 853.0.

Example 25: Synthesis of (glycyloxy)methyl4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indole-1-carboxylate

Step a: A mixture of iodomethyl4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indole-1-carboxylate(0.080 g, 0.10 mmol), (tert-butoxycarbonyl)glycine (0.056 g, 0.32 mmol)and diisopropylethylamine (0.088 mL, 0.53 mmol) in dichloromethane (3mL) was heated to 45° C. for 1.5 h. It was cooled to room temperature,concentrated under reduced pressure to afford(((tert-butoxycarbonyl)glycyl)oxy)methyl4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indole-1-carboxylate.MS: (ES) m/z calculated for C₃₉H₄₂F₄N₇O₇[M+H]⁺ 796.3, found 796.3.

Step b: A mixture of (((tert-butoxycarbonyl)glycyl)oxy)methyl4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indole-1-carboxylate(˜0.10 mmol) and 4 M HCl solution in dioxane (1.5 mL, 6 mmol) indichloromethane (3 mL) was stirred at room temperature for 1.5 h. Themixture was concentrated under reduced pressure and purified by silicagel flash chromatography (0 to 100% EtOAc in hexanes followed by 0 to80% MeOH in EtOAc). The pure fractions were combined, cooled to 0° C.,charged with 2 M HCl solution in ether (1 mL, 2 mmol) and concentratedunder reduced pressure to yield (glycyloxy)methyl4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indole-1-carboxylateas HCl salt. 1H NMR (400 MHz, CD₃OD) δ 8.59 (s, 2H), 7.78-7.83 (m, 1H),7.34 (dd, J=7.2, 7.2 Hz, 1H), 7.18 (br s, 2H), 6.60-6.68 (m, 2H), 6.17(s, 2H), 4.83 (br s, 2H), 4.39 (br s, 2H), 4.01 (br s, 2H), 3.97 (s,3H), 2.96-3.03 (m, 2H), 2.26 (br s, 4H), 1.96-2.03 (m, 2H), 1.20-1.26(m, 1H), 1.00 (br s, 6H); MS: (ES) m/z calculated for C₃₄H₃₄F₄N₇O₅[M+H]⁺ 696.2, found 696.2.

Example 26: Synthesis of ((L-valyl)oxy)methyl4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indole-1-carboxylate

Step a: A mixture of iodomethyl4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indole-1-carboxylate(0.080 g, 0.10 mmol), (tert-butoxycarbonyl)-L-valine (0.07 g, 0.32 mmol)and diisopropylethylamine (0.09 mL, 0.53 mmol) in dichloromethane (3 mL)was stirred at room temperature for 2 h. It was concentrated on a rotaryevaporator under reduced pressure and purified by silica gel flashchromatography (0 to 60% EtOAc in hexanes) to afford(((tert-butoxycarbonyl)-L-valyl)oxy)methyl4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indole-1-carboxylate;MS: (ES) m/z calculated for C₄₂H₄₈F₄N₇O₇[M+H]⁺ 838.4, found 838.8.

Step b: A mixture of (((tert-butoxycarbonyl)-L-valyl)oxy)methyl4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indole-1-carboxylate(31 mg, 0.037 mmol) and 4 M HCl solution in dioxane (0.5 mL, 2 mmol) indichloromethane (0.5 mL) was stirred at room temperature for 1 h. It wasconcentrated under reduced pressure and purified by silica gel flashchromatography (0 to 30% MeOH in CH₂Cl₂). The pure fractions werecombined, cooled to 0° C., charged with 2 M HCl solution in ether (0.5mL, 2 mmol) and concentrated under reduced pressure to yield((L-valyl)oxy)methyl4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indole-1-carboxylateas HCl salt. 1H NMR (400 MHz, CD₃OD) δ 8.60 (s, 2H), 7.81 (s, 1H), 7.36(dd, J=7.2, 7.2 Hz, 1H), 7.19 (br s, 2H), 6.62-6.72 (m, 2H), 6.24 (d,J=5.6 Hz, 1H), 6.13 (d, J=5.2 Hz, 1H), 5.49 (s, 1H), 4.82 (br s, 2H),4.41 (br s, 2H), 4.10 (s, 1H), 3.98 (s, 3H), 3.01 (s, 2H), 1.80-2.60 (m,5H), 0.60-1.40 (m, 14H); MS: (ES) m/z calculated for C₃₇H₄₀F₄N₇O₅ [M+H]⁺738.3, found 738.2.

Example 27: Synthesis of (glycyloxy)methyl4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indole-1-carboxylate

Step a: A mixture of iodomethyl4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indole-1-carboxylate(0.06 g, 0.07 mmol), (tert-butoxycarbonyl)glycine (0.04 g, 0.18 mmol)and diisopropylethylamine (0.08 mL, 0.48 mmol) in dichloromethane (1 mL)was stirred at 45° C. for 1.5 h. The mixture was cooled to roomtemperature and concentrated under reduced pressure to afford(((tert-butoxycarbonyl)glycyl)oxy)methyl4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indole-1-carboxylate.MS: (ES) m/z calculated for C₄₃H₄₅F₇N₅O₆[M+H]⁺ 860.3, found 860.3.

Step b: A mixture of (((tert-butoxycarbonyl)glycyl)oxy)methyl4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indole-1-carboxylate(˜0.07 mmol) and 4 M HCl solution in dioxane (1 mL, 4 mmol) in dioxane(2 mL) was stirred at room temperature for 2 h. The mixture wasconcentrated under reduced pressure and purified by HPLC (MeCN/H₂O, with0.1% TFA) to yield (glycyloxy)methyl4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indole-1-carboxylateas TFA salt. ¹H NMR (400 MHz, CDCl₃) δ 8.37 (d, J=7.6 Hz, 1H), 7.88-7.94(m, 2H), 7.59 (d, J=4.0 Hz, 1H), 7.20-7.30 (m, 2H), 7.07 (d, J=7.6 Hz,2H), 6.58-6.70 (m, 3H), 5.96 (s, 2H), 4.50-4.70 (m, 2H), 4.30 (br s,2H), 3.79 (s, 2H), 2.19 (br s, 4H), 1.83-2.03 (m, 8H), 0.98 (t, J=7.2Hz, 6H); MS: (ES) m/z calculated for C₃₈H₃₇F₇N₅O₄ [M+H]⁺ 760.3, found760.1.

Example 28: Synthesis of ((L-valyl)oxy)methyl4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indole-1-carboxylate

Step a: A mixture of iodomethyl4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indole-1-carboxylate(0.10 g, 0.12 mmol), (tert-butoxycarbonyl)-L-valine (0.08 g, 0.37 mmol)and diisopropylethylamine (0.10 mL, 0.61 mmol) in dichloromethane (3 mL)was stirred at 45° C. After 2 h, the mixture was cooled to roomtemperature, concentrated under reduced pressure and purified by silicagel flash chromatography (0 to 50% EtOAc in hexanes) to afford(((tert-butoxycarbonyl)-L-valyl)oxy)methyl4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indole-1-carboxylate.MS: (ES) m/z calculated for C₄₆H₅₁F₇N₅O₆[M+H]⁺ 902.3, found 902.3.

Step b: To a solution of (((tert-butoxycarbonyl)-L-valyl)oxy)methyl4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indole-1-carboxylate(25 mg, 0.028 mmol) in dichloromethane (0.3 mL) was added 4 M HCl indioxane (0.1 mL, 0.4 mmol). The mixture was stirred at room temperaturefor 3 h and then concentrated under reduced pressure to yield((L-valyl)oxy)methyl4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indole-1-carboxylateas HCl salt. ¹H NMR (400 MHz, CDCl₃) δ 9.33 (s, 1H), 8.99 (s, 2H),7.99-8.06 (m, 1H), 7.93 (s, 1H), 7.72 (s, 1H), 7.10-7.30 (m, 3H), 6.97(br s, 1H), 6.68-6.78 (m, 1H), 6.59-6.66 (m, 1H), 6.16-6.22 (m, 1H),5.90-5.98 (m, 1H), 4.69 (br s, 2H), 4.47 (br s, 1H), 4.03 (s, 1H),3.60-3.90 (m, 3H), 1.70-2.60 (m, 10H), 0.75-1.34 (m, 12H); MS: (ES) m/zcalculated for C₄₁H₄₃F₇N₅O₄ [M+H]⁺ 802.3, found 802.2.

Example 29: Synthesis of ((4-((dimethylamino)methyl)benzoyl)oxy)methyl4-(5-(2,4-bis(trifluoromethyl)-benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indole-1-carboxylate

A mixture of dimethylamine (0.40 mL, saturated in dichloromethane), HOAc(0.80 mL), ((4-formylbenzoyl)oxy)methyl4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indole-1-carboxylate(0.080 g, 0.096 mmol) and NaBH(OAc)₃ (0.200 g, 0.94 mmol) indichloromethane was stirred at room temperature for 1 h. The mixture waspoured into saturated aqueous NaHCO₃ solution and extracted with EtOAc.The organic layer was separated, dried over Na₂SO₄, concentrated underreduced pressure and purified by silica gel flash chromatography (0 to100% EtOAc in hexanes followed by 0 to 30% MeOH in EtOAc) to afford((4-((dimethylamino)methyl)benzoyl)oxy)methyl4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indole-1-carboxylate.¹H NMR (400 MHz, CDCl₃) δ 8.15 (d, J=8.0 Hz, 1H), 8.03 (d, J=7.2 Hz,2H), 7.86 (s, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.66 (m, 1H), 7.40 (d, J=7.6Hz, 2H), 7.25 (m, 1H), 7.07 (d, J=7.6 Hz, 2H), 6.77 (m, 1H), 6.62 (m,1H), 6.56 (m, 1H), 6.23 (s, 2H), 4.12 (s, 2H), 3.63 (s, 2H), 3.47 (s,2H), 2.23 (s, 6H), 2.10-2.40 (m, 4H), 1.55 (s, 6H), 1.01 (t, J=7.4 Hz,6H); MS: (ES) m/z calculated for C₄₆H₄₅F₇N₅O₄ [M+H]⁺ 864.3, found 864.2.

Example 30: Synthesis of ((dimethylglycyl)oxy)methyl4-(5-(2,4-bis(trifluoromethyl)-benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indole-1-carboxylate

A mixture of iodomethyl4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indole-1-carboxylate(0.03 g, 0.04 mmol) and tetrabutylammonium dimethylglycinate (20 mg,0.06 mmol) in THF (0.6 mL) was stirred at room temperature for 0.5 h.The mixture was concentrated under reduced pressure and purified by HPLC(MeCN/H₂O, with 1% HOAc) to yield ((dimethylglycyl)oxy)methyl4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indole-1-carboxylate.¹H NMR (400 MHz, CD₃OD) δ 8.21 (d, J=8.4 Hz, 1H), 7.91-7.96 (m, 2H),7.80 (d, J=4.0 Hz, 1H), 7.34 (dd, J=7.6, 7.6 Hz, 1H), 7.17 (d, J=7.6 Hz,2H), 6.81-6.87 (m, 1H), 6.65-6.72 (m, 2H), 6.12 (s, 2H), 4.23 (s, 2H),4.17 (s, 2H), 3.69 (s, 2H), 2.90 (s, 6H), 2.17-2.36 (m, 4H), 1.57 (s,6H), 1.02 (t, J=7.4 Hz, 6H); MS: (ES) m/z calculated for C₄₀H₄₁F₇N₅O₄[M+H]⁺ 788.3, found 788.2.

Example 31: Synthesis of ((dimethoxyphosphoryl)oxy)methyl4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indole-1-carboxylate

A mixture of iodomethyl4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indole-1-carboxylate(40 mg, 0.037 mmol) and tetrabutylammonium dimethylphosphate (30 mg,0.08) mmol) in THF (6 mL) was stirred at room temperature for 1.5 h.After completion, the mixture was diluted with EtOAc, washed with brine,and dried over MgSO₄. The solvent was removed under reduced pressure andthe residue was purified by silica gel flash chromatography (5 to 20%EtOAc in hexanes) to yield ((dimethoxyphosphoryl)oxy)methyl4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indole-1-carboxylate.¹H NMR (400 MHz, CD₃OD) δ 8.13 (d, J=8.2 Hz, 1H), 7.75-7.88 (m, 2H),7.66-7.68 (m, 1H), 7.23-7.27 (m, 1H), 7.07-7.09 (m, 2H), 6.77 (dd,J=8.4, 11.8 Hz, 1H), 6.59-6.66 (m, 2H), 5.81 (d, J=14.1 Hz, 2H), 4.12(s, 2H), 3.79 (s, 3H), 3.76 (s, 3H), 3.70 (s, 2H), 2.14-2.38 (m, 4H),1.56 (s, 6H), 1.02 (t, J=7.6 Hz, 6H). MS: (ES) m/z calculated forC₃₈H₃₉F₇N₄O₆P [M+H]⁺ 811.2, found 811.2.

Example 32: Synthesis of(4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indol-1-yl)methanol

A mixture of2-(2,6-diethylphenyl)-3-(6-fluoro-7-methoxy-1H-indol-4-yl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine(200 mg, 0.35 mmol), di-tert-butyl (chloromethyl) phosphate (183 mg,0.35 mmol) and NaH (100 mg, 60% in mineral oil, 2.5 mmol) in DMF (5 mL)was stirred at room temperature for 2 h. The mixture was poured intowater and extracted with EtOAc. The organic layer was separated, driedover Na₂SO₄, concentrated under reduced pressure and purified by silicagel flash chromatography (0 to 80% EtOAc in hexanes) to afford(4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)nethanol.¹H NMR (400 MHz, CDCl₃) δ 8.48 (s, 2H), 7.24 (dd, J=7.2, 7.2 Hz, 1H),7.15 (d, J=3.2 Hz, 1H), 7.00-7.10 (m, 2H), 6.44 (d, J=12.8 Hz, 1H), 6.33(d, J=3.2 Hz, 1H), 5.59 (d, J=8.0 Hz, 2H), 4.80 (s, 2H), 4.35 (s, 2H),4.11 (d, J=2.4 Hz, 3H), 3.71 (t, J=8.2 Hz, 1H), 3.02 (t, J=5.8 Hz, 2H),2.30 (br s, 4H), 1.02 (br s, 6H). MS: (ES) m/z calculated forC₃₁H₃₁F₄N₆O₂ [M+H]⁺ 595.2, found 595.5.

Example 33: Synthesis of(4-(2-(2,6-diethylphenyl)-5-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-5-fluoro-1H-indol-7-yl)methylglycinate hydrochloride

To a vial with DMF (3.0 mL) was charged with(4-(2-(2,6-diethylphenyl)-5-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-5-fluoro-1H-indol-7-yl)methanol(100 mg, 0.18 mmol), (tert-butoxycarbonyl)glycine (61 mg, 0.35 mmol),HATU (134 mg, 0.35 mmol) and diisopropylethylamine (68 mg, 0.52 mmol).The mixture was stirred at room temperature for 24 h. After completion,the reaction was quenched with H₂O and the crude was purified by silicagel chromatography (10 to 50% EtOAc in hexanes) and concentrated invacuo. The residue was then dissolved in dichloromethane (3.0 mL) andtreated with 4 N HCl in dioxane (2.0 mL) at room temperature for 2 h.After completion of the reaction, the solvent was removed and theresidue was triturated with dichloromethane to give the(4-(2-(2,6-diethylphenyl)-5-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-5-fluoro-1H-indol-7-yl)methylglycinate hydrochloride. ¹H NMR (400 MHz, CD₃OD) δ 11.07 (bs, 1H), 8.56(bs, 2H), 7.47-7.50 (m, 1H), 7.19-7.26 (m, 2H), 6.91 (dd, J=1.9, 3.1 Hz,1H), 6.85 (d, J=10.9 Hz 1H), 6.40-6.43 (m, 1H), 5.53 (s, 2H), 4.90 (d,J=16.1 Hz, 1H), 4.62 (d, J=16.0 Hz, 1H), 4.42-4.50 (m, 1H), 4.25-4.35(m, 1H), 3.90 (s, 2H), 3.76 (s, 2H), 3.00 (t, J=5.9 Hz, 2H), 2.43-2.50(m, 2H), 2.12-2.20 (m, 1H), 1.90-1.98 (m, 1H), 1.22 (t, J=7.8 Hz, 3H),0.73 (t, J=7.4 Hz, 3H) MS: (ES) m/z calculated for C₃₂H₃₁F₄N₇O₂ [M+H]⁺622.3, found 622.2

Example 34: Synthesis of(4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-5-fluoro-1H-indol-7-yl)methyl-L-valinatehydrochloride

Step a: To a vial with DMF (3.0 mL) was charged with(4-(2-(2,6-diethylphenyl)-5-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-5-fluoro-1H-indol-7-yl)methanol(100 mg, 0.18 mmol), (tert-butoxycarbonyl)valine (77 mg, 0.35 mmol),HATU (134 mg, 0.35 mmol) and diisopropylethylamine (68 mg, 0.53 mmol).The reaction mixture was stirred at 50° C. for 24 h. After completion,the mixture was quenched with H₂O and the crude was purified by silicagel chromatography (10 to 50% EtOAc in hexanes) and concentrated invacuo to give(4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-5-fluoro-1H-indol-7-yl)methyl(tert-butoxycarbonyl)-L-valinate.MS: (ES) m/z calculated for C₄₀H₄₅F₄N₇O₄ [M+H]⁺ 764.4, found 764.3.

Step b: To a stirred solution of(4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-5-fluoro-1H-indol-7-yl)methyl(tert-butoxycarbonyl)-L-valinate (60 mg, 0.08 mmol) in dichloromethane(5 mL) was added 4 N HCl in dioxane (0.2 mL, 0.8 mmol). The resultingmixture was stirred at room temperature for 2 h. After completion, thereaction mixture was diluted with water and saturated aqueous NaHCO₃,extracted with dichloromethane, washed with brine, and dried over MgSO₄.The solvent was removed under reduced pressure and the residue waspurified by HPLC (MeCN/H₂O, with 0.1% TFA) to give the desired product.The material was converted to HCl salt to give(4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-5-fluoro-1H-indol-7-yl)methyl-L-valinatehydrochloride. ¹H NMR (400 MHz, DMSO-d₆) δ 11.65 (bs, 1H), 8.61-8.72 (m,2H), 8.42 (bs, 2H), 7.56 (bs, 1H), 7.15-7.25 (m, 2H), 6.88-6.98 (m, 2H),6.33 (s, 1H), 5.42-5.55 (m, 2H), 4.74 (dd, J=6.2, 15.2 Hz, 1H), 4.57 (d,J=15.7 Hz, 1H), 4.35-4.45 (m, 1H), 4.15-4.20 (m, 1H), 3.92-4.05 (m, 1H),2.85-2.95 (m, 2H), 2.28-2.40 (m, 2H), 2.00-2.20 (m, 2H), 1.85-1.92 (m,1H), 1.12 (t, J=7.4 Hz, 3H), 0.83-0.90 (m, 6H), 0.61-0.63 (m, 3H). MS:(ES) m/z calculated for C₃₅H₃₇F₄N₇O₂ [M+H]⁺ 664.3, found 664.2.

Example 35: Synthesis of4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-5-fluoro-1H-indol-7-yl)methyl(S)-2,5-diaminopentanoate hydrochloride

Step a: To a vial with DMF (3.0 mL) was charged with(4-(2-(2,6-diethylphenyl)-5-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-5-fluoro-1H-indol-7-yl)methanol(110 mg, 0.19 mmol), 2,5-bis(tert-butoxycarbonylamino)pentanoic acid (96mg, 0.29 mmol), HATU (149 mg, 0.39 mmol) and diisopropylethylamine (75mg, 1.17 mmol). The reaction was stirred at room temperature for 24 h.After completion, the mixture was quenched with H₂O and the crude waspurified by silica gel chromatography (10 to 100% EtOAc in hexanes)concentrated dried under vacuum to give4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-5-fluoro-1H-indol-7-yl)methyl(S)-2,5-bis((tert-butoxycarbonyl)amino)pentanoate. MS: (ES) m/zcalculated for C₄₅H₅₄F₄N₈O₆ [M+H]⁺ 879.41, found 879.5

Step b: To a stirred solution of4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-5-fluoro-1H-indol-7-yl)methyl-(S)-2,5-bis((tert-butoxycarbonyl)-amino)pentanoate(75 mg, 3.6 mmol) in dichloromethane (5 mL) was added 4 N HCl in dioxane(0.18 mL, 0.68 mmol). The resulting mixture was stirred at roomtemperature for 2 h. After completion, the reaction mixture was dilutedwith H₂O and saturated aqueous NaHCO₃, extracted with dichloromethane,washed with brine and dried over MgSO₄. The solvent was removed underreduced pressure and the residue was purified by HPLC (MeCN/H₂O, with0.1% TFA) to give the desired product. The material was converted to HClsalt to give(4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-5-fluoro-1H-indol-7-yl)methyl(S)-2,5-diaminopentanoate hydrochloride. ¹H NMR (400 MHz, DMSO-d₆) δ11.77 (bs, 1H), 8.50-8.65 (m, 4H), 7.90-8.25 (m, 2H), 7.55 (bs, 1H),7.15-7.25 (m, 2H), 6.97 (dd, J=1.9, 10.9 Hz, 1H), 6.91 (d, J=7.4 Hz 1H),6.34 (bs, 1H), 5.35-5.54 (m, 2H), 4.73 (d, J=15.7 Hz, 1H), 4.56 (d,J=16.0 Hz, 1H), 4.38-4.45 (m, 2H), 4.05-4.25 (m, 2H), 2.85-3.00 (m, 2H),2.75-2.80 (m, 2H), 2.31-2.40 (m, 2H), 1.95-2.10 (m, 1H), 1.65-1.78 (m,4H), 1.12 (t, J=7.4 Hz, 3H), 0.65 (t, J=7.4 Hz, 3H), MS: (ES) m/zcalculated for C₃₅H₃₈F₄N₈O₂ [M+H]⁺ 679.3, found 679.2.

Example 36: Synthesis of(4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-5-fluoro-W-indol-7-yl)methylL-lysinate hydrochloride

Example 36 was prepared similar to the procedure as described in Example35 using N₂,N₆-bis(tert-butoxycarbonyl)-L-lysine and(4-(2-(2,6-diethylphenyl)-5-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-5-fluoro-1H-indol-7-yl)methanol.¹H NMR (400 MHz, DMSO-d₆) δ 11.71 (bs, 1H), 8.50-8.75 (m, 4H), 7.89 (bs,2H), 7.56 (t, J=2.8 Hz 1H), 7.15-7.25 (m, 2H), 6.94 (d, J=11.0 Hz, 1H),6.91 (d, J=7.1 Hz 1H), 6.30-6.35 (m, 1H), 5.38-5.54 (m, 2H), 4.73 (d,J=15.6 Hz, 1H), 4.57 (d, J=15.7 Hz, 1H), 4.35-4.45 (m, 1H), 4.15-4.30(m, 1H), 4.05-4.15 (m, 2H), 2.85-3.00 (m, 2H), 2.65-2.75 (m, 2H),2.30-2.42 (m, 2H), 2.00-2.15 (m, 1H), 1.75-1.90 (m, 3H), 1.25-1.60 (m,3H), 1.12 (t, J=7.4 Hz, 3H), 0.65 (t, J=7.4 Hz, 3H), MS: (ES) m/zcalculated for C₃₆H₄₀F₄N₈O₂ [M+H]⁺ 693.3, found 693.3.

Example 37: Synthesis of(4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-5-fluoro-1H-indol-7-yl)methyl4-aminobutanoate hydrochloride

Example 37 was prepared similar to the procedure as described in Example35 using 4-((tert-butoxycarbonyl)amino)butanoic acid and(4-(2-(2,6-diethylphenyl)-5-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-5-fluoro-1H-indol-7-yl)methanol¹H NMR (400 MHz, DMSO-d₆) δ 11.98 (s, 1H), 8.52-8.72 (m, 2H), 7.79 (bs,2H), 7.52 (t, J=3.1 Hz 1H), 7.14-7.30 (m, 2H), 6.91 (dd, J=1.6, 7.4 Hz,1H), 6.84 (d, J=10.9 Hz, 1H), 6.31 (dd, J=1.9, 3.1 Hz, 1H), 5.27 (d,J=3.1 Hz, 2H), 4.74 (d, J=15.6 Hz, 1H), 4.57 (d, J=15.6 Hz, 1H),4.35-4.50 (m, 2H), 4.15-4.25 (m, 2H), 2.85-3.00 (m, 2H), 2.76-2.84 (m,2H), 2.31-2.40 (m, 2H), 2.0-2.15 (m, 1H), 1.76-1.90 (m, 3H), 1.12 (t,J=7.4 Hz, 3H), 0.65 (t, J=7.5 Hz, 3H), MS: (ES) m/z calculated forC₃₄H₃₅F₄N₇O₂ [M+H]⁺ 650.3, found 650.3.

Example 38: Synthesis of(4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-5-fluoro-1H-indol-7-yl)methyl-L-histidinatehydrochloride

Example 38 was prepared similar to the procedure as described in Example35 using (tert-butoxycarbonyl)-L-histidine and(4-(2-(2,6-diethylphenyl)-5-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-5-fluoro-1H-indol-7-yl)methanol.¹H NMR (400 MHz, DMSO-d₆) δ 11.76 (br s, 1H), 9.01 (d, J=3.9 Hz 1H),8.55-8.75 (m, 4H), 7.55 (d, J=2.8 Hz 1H), 7.48 (s, 1H), 7.15-7.25 (m,2H), 6.90-6.98 (m, 2H), 6.34 (bs, 1H), 5.37-5.54 (m, 2H), 4.75 (dd,J=2.7, 15.6 Hz, 1H), 4.56 (d, J=15.6 Hz, 1H), 4.35-4.45 (m, 2H),4.15-4.25 (m, 1H), 3.25-3.35 (m, 2H), 2.85-2.95 (m, 3H), 2.30-2.42 (m,2H), 2.00-2.10 (m, 1H), 1.82-1.90 (m, 1H), 1.13 (t, J=7.8 Hz, 3H), 0.65(t, J=7.8 Hz, 3H). MS: (ES) m/z calculated for C₃₆H₃₅F₄N₉O₂[M+H]⁺ 702.3,found 701.9.

Example 39: Synthesis of(S)-3-amino-4-((4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-5-fluoro-1H-indol-7-yl)methoxy)-4-oxobutanoicacid hydrochloride

Example 39 was prepared similar to the procedure as described in Example35 using(S)-4-(tert-butoxy)-2-((tert-butoxycarbonyl)amino)-4-oxobutanoic acidand(4-(2-(2,6-diethylphenyl)-5-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-5-fluoro-1H-indol-7-yl)methanol.¹H NMR (400 MHz, DMSO-d₆) δ 11.65 (bs, 1H), 8.60-8.75 (m, 2H), 8.46 (bs,3H), 7.52 (t, J=2.9 Hz 1H), 7.15-7.25 (m, 2H), 6.90 (d, J=7.8 Hz, 1H),6.87 (bs, 1H), 6.31 (bs, 1H), 5.25-5.40 (m, 2H), 4.57 (d, J=15.7 Hz,1H), 4.35-4.45 (m, 1H), 4.15-4.30 (m, 2H), 3.53 (s, 2H), 2.99 (d, J=5.5Hz, 1H), 2.85-2.92 (m, 2H), 2.30-2.38 (m, 2H), 2.00-2.15 (m, 1H),1.82-1.90 (m, 1H), 1.11 (t, J=7.8 Hz, 3H), 0.65 (t, J=7.8 Hz, 3H). MS:(ES) m/z calculated for C₃₄H₃₃F₄N₇O₂[M+H]⁺ 680.3, found 680.1.

Example 40: Synthesis of(4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-5-fluoro-1H-indol-7-yl)methylL-valylglycinate hydrochloride

Step a: To a vial with DMF (3.0 mL) was charged with(4-(2-(2,6-diethylphenyl)-5-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-5-fluoro-1H-indol-7-yl)methanol(150 mg, 0.27 mmol), (tert-butoxycarbonyl)-L-valylglycine (145 mg, 0.53mmol), EDCI (101 mg, 0.53 mmol), HOBT (61 mg, 0.39 mmol) and DIPEA (102mg, 0.77 mmol). The mixture was stirred at 50° C. for 24 h. Aftercompletion of the reaction, the reaction was worked up and the crude waspurified by silica gel chromatography (10 to 60% EtOAc in hexanes) togive(4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-5-fluoro-1H-indol-7-yl)methyl(tert-butoxycarbonyl)-L-valylglycinate.

Step b: To a stirred solution of(4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-5-fluoro-1H-indol-7-yl)methyl-(tert-butoxycarbonyl)-L-valylglycinate(180 mg, 0.02 mmol) in dichloromethane (5 mL) was added 4 N HCl solutionin dioxane (0.25 mL, 0.1 mmol). The resulting mixture was stirred atroom temperature for 5 h. After completion, the solvent was diluted withwater and saturated aqueous NaHCO₃, extracted with dichloromethane,washed with brine and dried over Na₂SO₄. The solvent was removed underreduced presure and the crude was purified by column chromatography(20-100% EtOAc/hexane) to give the desired product, which is convertedto HCl salt to give(4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-5-fluoro-1H-indol-7-yl)methyl-L-valylglycinatehydrochloride. 1H NMR (400 MHz, DMSO-d₆) δ 11.58 (br s, 1H), 8.85 (br s,1H), 8.60-8.75 (m, 2H), 8.09 (br s, 2H), 7.53 (t, J=3.1 Hz 1H),7.12-7.25 (m, 2H), 6.90 (d, J=6.3 Hz, 1H), 6.86 (d, J=10.9 Hz, 1H), 6.31(t, J=2.8 Hz, 1H), 5.25-5.35 (m, 2H), 4.72 (d, J=15.9 Hz, 1H), 4.57 (d,J=16.3 Hz, 1H), 4.40-4.45 (m, 1H), 4.10-4.25 (m, 2H), 3.91 (dd, J=5.1,17.2 Hz, 1H), 3.59 (t, J=0.8 Hz, 1H), 2.85-2.92 (m, 2H), 2.31-2.40 (m,2H), 1.90-2.08 (m, 2H), 1.80-1.90 (m, 1H), 1.12 (t, J=7.8 Hz, 3H),0.80-0.85 (m, 6H), 0.65 (t, J=7.8 Hz, 3H), MS: (ES) m/z calculated forC₃₇H₄₀F₄N₈O₃ [M+H]⁺ 721.3, found 721.3.

Example 41: Synthesis of(4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-5-fluoro-1H-indol-7-yl)methylL-isoleucinate hydrochloride

Example 41 was prepared similar to the procedure as described in Example35 using (tert-butoxycarbonyl)-L-isoleucine and(4-(2-(2,6-diethylphenyl)-5-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-5-fluoro-1H-indol-7-yl)methanol.¹H NMR (400 MHz, DMSO-d₆) δ 11.63 (br s, 1H), 8.60-8.75 (m, 2H), 8.42(br s, 2H), 7.43-7.60 (m, 1H), 7.14-7.25 (m, 2H), 6.85-6.95 (m, 2H),6.30-6.35 (m, 1H), 5.38-5.45 (m, 2H), 4.76 (dd, J=5.8, 16.0 Hz, 1H),4.56 (d, J=15.7 Hz, 1H), 4.35-4.45 (m, 1H), 4.15-4.20 (m, 1H), 3.98-4.05(m, 1H), 2.82-2.97 (m, 2H), 2.30-2.42 (m, 3H), 2.00-2.10 (m, 1H),1.80-1.90 (m, 2H), 1.25-1.35 (m, 1H), 1.12 (t, J=7.4 Hz, 3H), 0.72-0.85(m, 6H), 0.65 (t, J=7.4 Hz, 3H). MS: (ES) m/z calculated forC₃₆H₃₉F₄N₇O₂[M+H]⁺ 678.3, found 678.3.

Example 42: Synthesis of(4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-5-fluoro-1H-indol-7-yl)methylL-alaninate hydrochloride

Example 42 was prepared similar to the procedure as described in Example35 using (tert-butoxycarbonyl)-L-alanine and(4-(2-(2,6-diethylphenyl)-5-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-5-fluoro-1H-indol-7-yl)methanol.¹H NMR (400 MHz, DMSO-d₆) δ 11.62 (br s, 1H), 8.60-8.75 (m, 2H), 8.35(br s, 2H), 7.56 (t, J=2.7 Hz, 1H), 7.12-7.25 (m, 2H), 6.85-6.95 (m,2H), 6.30-6.35 (m, 1H), 5.35-5.50 (m, 2H), 4.73 (d, J=17.0 Hz, 1H), 4.56(d, J=15.76 Hz, 1H), 4.35-4.45 (m, 1H), 4.15-4.22 (m, 2H), 2.85-2.95 (m,2H), 2.25-2.40 (m, 2H), 2.00-2.10 (m, 1H), 1.82-1.90 (m, 1H), 1.38 (dd,J=2.4, 7.5 Hz, 3H), 1.12 (t, J=7.8 Hz, 3H), 0.65 (dd, J=7.2, 15.6 Hz,3H). MS: (ES) m/z calculated for C₃₃H₃₃F₄N₇O₂[M+H]⁺ 636.3, found 636.2.

Example 43: Synthesis of4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-5-fluoro-1H-indol-7-yl)methyl-L-phenylalaninatehydrochloride

Example 43 was prepared similar to the procedure as described in Example35 using (tert-butoxycarbonyl)-L-phenylalanine and(4-(2-(2,6-diethylphenyl)-5-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-5-fluoro-1H-indol-7-yl)methanol.¹H NMR (400 MHz, DMSO-d₆) δ 11.55 (br s, 1H), 8.60-8.75 (m, 2H),8.45-8.52 (m, 2H), 7.52-7.58 (m, 1H), 7.10-7.25 (m, 7H), 6.88-6.95 (m,1H), 6.71 (dd, J=11.4, 24.3 Hz, 1H), 6.30-6.38 (m, 1H), 5.35-5.45 (m,2H), 4.73 (d, J=15.9 Hz, 1H), 4.57 (d, J=16.0 Hz, 1H), 4.35-4.45 (m,2H), 4.15-4.22 (m, 1H), 3.05-3.15 (m, 2H), 2.85-2.95 (m, 2H), 2.30-2.45(m, 2H), 2.00-2.15 (m, 1H), 1.82-1.90 (m, 1H), 1.13 (t, J=7.4 Hz, 3H),0.64 (t, J=7.8 Hz, 3H). MS: (ES) m/z calculated for C₃₉H₃₇F₄N₇O₂ [M+H]⁺712.3, found 712.2.

Example 44: Synthesis of(S)-2-amino-5-((4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-5-fluoro-1H-indol-7-yl)methoxy)-5-oxopentanoicacid hydrochloride

Example 44 was prepared similar to the procedure as described in Example35 using(S)-5-(tert-butoxy)-4-((tert-butoxycarbonyl)amino)-5-oxopentanoic acidand(4-(2-(2,6-diethylphenyl)-5-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-5-fluoro-1H-indol-7-yl)methanol.¹H NMR (400 MHz, DMSO-d₆) δ 11.61 (br s, 1H), 8.62-8.75 (m, 2H),8.35-8.45 (m, 3H), 7.52 (t, J=2.7 Hz 1H), 7.12-7.25 (m, 2H), 6.90 (dd,J=7.8, 11.6 Hz, 1H), 6.84 (d, J=11.0 Hz, 1H), 6.31 (q, J=2.0 Hz, 1H),5.23-5.31 (m, 2H), 4.74 (d, J=16.0 Hz, 1H), 4.57 (d, J=16.0 Hz, 1H),4.35-4.45 (m, 1H), 3.85-4.00 (m, 2H), 2.85-2.95 (m, 2H), 2.45-2.65 (m,2H), 2.25-2.40 (m, 2H), 1.85-2.10 (m, 3H), 1.80-1.95 (m, 1H), 1.12 (t,J=7.8 Hz, 3H), 0.64 (t, J=7.8 Hz, 3H). MS: (ES) m/z calculated forC₃₅H₃₅F₄N₇O₄ [M+H]⁺ 694.3, found 694.2.

Example 45: Synthesis of(S)-2-acetamido-5-((4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-5-fluoro-1H-indol-7-yl)methoxy)-5-oxopentanoicacid

To a stirred solution of(S)-2-amino-5-((4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-5-fluoro-1H-indol-7-yl)methoxy)-5-oxopentanoicacid (70 mg, 0.113 mmol) in dichloromethane (3.0 mL) at room temperaturewere added pyridine (27 mg, 0.4 mmol) and acetic anhydride (30 mg, 0.34mmol). The reaction mixture was stirred at room temperature for 1 h.After completion, the solvent was removed and the crude material waspurified by HPLC (MeCN/H₂O, with 0.1% TFA) to give the(S)-2-acetamido-5-((4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-5-fluoro-1H-indol-7-yl)methoxy)-5-oxopentanoicacid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.53 (br s, 1H), 8.55-8.80 (m, 2H),8.12 (d, J=7.8 Hz, 1H), 7.53 (t, J=2.7 Hz, 1H), 7.15-7.25 (m, 2H), 6.91(d, J=7.5 Hz, 1H), 6.85 (d, J=10.2 Hz, 1H), 6.31 (t, J=10.2 Hz, 1H),5.25 (d, J=2.7 Hz, 2H), 4.75 (d, J=16.0 Hz, 1H), 4.58 (d, J=16.0 Hz,1H), 4.37-4.45 (m, 1H), 4.18-4.25 (m, 2H), 3.45-3.85 (m, 1H), 2.85-2.98(m, 2H), 2.30-2.45 (m, 4H), 1.95-2.10 (m, 2H), 1.85-1.92 (m, 1H), 1.81(s, 3H), 1.70-1.78 (m, 1H), 1.12 (t, J=7.8 Hz, 3H), 0.65 (t, J=7.8 Hz,3H), MS: (ES) m/z calculated for C₃₇H₃₇F₄N₇O₅ [M+H]⁺ 736.3, found 736.2.

Example 46: Synthesis of(S)-4-amino-5-((4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-5-fluoro-1H-indol-7-yl)methoxy)-5-oxopentanoicacid hydrochloride

Example 46 was prepared similar to the procedure as described in Example35 using(S)-5-(tert-butoxy)-2-((tert-butoxycarbonyl)amino)-5-oxopentanoic acidand(4-(2-(2,6-diethylphenyl)-5-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-5-fluoro-1H-indol-7-yl)methanol.¹H NMR (400 MHz, DMSO-d₆) δ 11.56 (br s, 1H), 8.60-8.75 (m, 2H),8.30-8.45 (m, 2H), 7.56 (t, J=2.7 Hz 1H), 7.15-7.25 (m, 2H), 6.90-6.98(m, 2H), 6.30-6.38 (m, 1H), 5.36-5.52 (m, 2H), 4.74 (dd, J=5.6, 16.0 Hz,1H), 4.57 (d, J=15.7 Hz, 1H), 4.35-4.45 (m, 1H), 4.05-4.25 (m, 2H),3.35-4.00 (m, 1H), 2.85-2.95 (m, 2H), 2.30-2.45 (m, 4H), 1.95-2.10 (m,3H), 1.83-1.95 (m, 1H), 1.12 (t, J=7.8 Hz, 3H), 0.65 (dd, J=7.5, 14.9Hz, 3H), MS: (ES) m/z calculated for C₃₅H₃₅F₄N₇O₄ [M+H]⁺ 694.3, found694.2.

Example 47: Synthesis of(4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-5-fluoro-1H-indol-7-yl)methylglycyl-L-valinate hydrochloride

Example 47 was prepared similar to the procedure as described in Example40 using (tert-butoxycarbonyl)glycyl-L-valine and(4-(2-(2,6-diethylphenyl)-5-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-5-fluoro-1H-indol-7-yl)methanol.¹H NMR (400 MHz, DMSO-d₆) δ 11.60 (br s, 1H), 8.60-8.75 (m, 2H), 8.05(br s, 2H), 7.55 (br s, 1H), 7.14-7.25 (m, 2H), 6.90-6.95 (m, 1H), 6.86(dd, J=2.0, 11.0 Hz, 1H), 6.32 (t, J=2.3 Hz, 1H), 5.30-5.45 (m, 2H),4.78 (d, J=3.5 Hz, 1H), 4.74 (d, J=3.1 Hz, 1H), 4.58 (d, J=16.0 Hz, 2H),4.35-4.45 (m, 2H), 4.15-4.25 (m, 1H), 3.55-3.70 (m, 2H), 2.85-2.96 (m,2H), 2.30-2.45 (m, 2H), 2.00-2.10 (m, 2H), 1.83-1.90 (m, 1H), 1.12 (t,J=7.5 Hz, 3H), 0.75-0.85 (m, 6H), 0.63 (t, J=7.4 Hz, 3H). MS: (ES) m/zcalculated for C₃₇H₄₀F₄N₈O₃ [M+H]⁺ 721.3, found 721.2.

Example 48: Synthesis of(4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-5-fluoro-1H-indol-7-yl)methylL-alanyl-L-alaninate hydrochloride

Example 48 was prepared similar to the procedure as described in Example40 using (tert-butoxycarbonyl)-L-alanyl-L-alanine and(4-(2-(2,6-diethylphenyl)-5-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-5-fluoro-1H-indol-7-yl)methanol.¹H NMR (400 MHz, DMSO-d₆) δ 11.58 (br s, 1H), 8.50-8.95 (m, 3H), 8.10(br s, 2H), 7.53 (br s, 1H), 7.12-7.25 (m, 2H), 6.90 (d, J=7.5 Hz, 1H),6.84 (dd, J=6.0, 10.6 Hz, 1H), 6.31 (br s, 1H), 5.25-5.38 (m, 2H), 4.73(d, J=16.5 Hz, 1H), 4.57 (d, J=16.0 Hz, 1H), 4.35-4.45 (m, 2H),4.15-4.25 (m, 1H), 3.70-3.92 (m, 1H), 2.85-2.95 (m, 2H), 2.30-2.38 (m,2H), 2.00-2.10 (m, 1H), 1.80-1.87 (m, 1H), 1.30 (t, J=5.6 Hz, 3H),1.10-1.18 (m, 6H), 0.60-0.66 (m, 3H). MS: (ES) m/z calculated forC₃₆H₃₈F₄N₈O₃ [M+H]⁺ 707.3, found 707.2.

Example 49: Synthesis of4-(((4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-5-fluoro-1H-indol-7-yl)methoxy)methyl)-5-methyl-1,3-dioxol-2-one

To a stirred solution of(4-(2-(2,6-diethylphenyl)-5-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-5-fluoro-1H-indol-7-yl)methanol(100 mg, 0.18 mmol) in dichloromethane (4.0 mL) at room temperature wereadded diisopropylethylamine (151 mg, 1.2 mmol) and4-(chloromethyl)-5-methyl-1,3-dioxol-2-one (150 mg, 0.78 mmol). Thereaction was stirred at room temperature for 24 h. After completion, themixture was quenched with H₂O and the crude was purified by HPLC(MeCN/H₂O, with 0.1% TFA) to give the4-(((4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-5-fluoro-1H-indol-7-yl)methoxy)methyl)-5-methyl-1,3-dioxol-2-one.¹H NMR (400 MHz, CDCl₃) δ 9.17 (br s, 1H), 8.47 (br s, 2H), 7.32-7.40(m, 1H), 7.10-7.35 (m, 2H), 6.85 (d, J=7.4 Hz, 1H), 6.63 (d, J=10.5 Hz,1H), 6.35-6.45 (m, 1H), 5.49 (d, J=15.1 Hz, 1H), 5.29 (d, J=15.5 Hz,1H), 4.87 (dd, J=4.3, 16.1 Hz, 1H), 4.66 (dd, J=6.0, 16.5 Hz, 1H),4.38-4.45 (m, 1H), 4.25-4.35 (m, 1H), 3.04 (t, J=5.8 Hz, 1H), 2.38-2.55(m, 2H), 2.35 (s, 3H), 2.11-2.25 (m, 2H), 1.85-2.05 (m, 2H), 0.91-1.12(m, 3H), 0.70-0.89 (m, 3H). MS: (ES) m/z calculated for C₃₅H₃₂F₄N₆O₄[M+H]⁺ 677.2, found 677.3.

Example 50: Synthesis of(4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-5-fluoro-1H-indol-7-yl)methyldihydrogen phosphate

Step a: To a stirred solution of of(4-(2-(2,6-diethylphenyl)-5-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-5-fluoro-1H-indol-7-yl)methanol(100 mg, 0.16 mmol) in dicloromethane (30 mL) at −20° C. was added PBr₃(95 mg, 0.32 mmol). The reaction mixture was allowed to warm to 0° C.and stirred for 2 h. After completion of the reaction, the solvent wasremoved in vacuo to give3-(7-(bromomethyl)-5-fluoro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridinewhich was used directly in the next step without further purification.

Step b: To a stirred solution of3-(7-(bromomethyl)-5-fluoro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine(85 mg, 1.24 mmol) in THF (4 mL) was added tetrabutylammoniumdi-tert-butyl phosphate (91 mg, 0.2 mmol). The reaction mixture wasstirred at room temperature for overnight. The reaction mixture wasconcentrated and the crude was purified by silica gel chromatography (10to 100% EtOAc in hexanes) to givedi-tert-butyl-((4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-5-fluoro-1H-indol-7-yl)methyl)phosphate.MS: (ES) m/z calculated for C₃₈H₄₅F₄N₆O₄P [M+H]⁺ 757.32, found 757.3.

Step c: To a stirred solution ofdi-tert-butyl-((4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-5-fluoro-1H-indol-7-yl)methyl)phosphate(70 mg, 0.92 mmol) in anhydrous dichloromethane (15 mL) at 0° C. wasadded TFA (52 mg, 0.46 mmol) dropwise over 5 min. The reaction mixturewas stirred at room temperature for 2 h. After completion of thereaction, the solvent was removed in vacuo and the residue was purifiedby HPLC (MeCN/H₂O, with 0.1% TFA) to give(4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-5-fluoro-1H-indol-7-yl)methyldihydrogen phosphate. 1H NMR (400 MHz, CD₃OD) δ 8.56 (br s, 2H), 7.43(d, J=3.2 Hz, 1H), 7.15-7.25 (m, 2H), 6.90 (d, J=5.9 Hz, 1H), 6.81 (d,J=11.3 Hz, 1H), 6.37 (d, J=3.1 Hz, 1H), 5.20-5.30 (m, 2H), 4.91 (d,J=16.1 Hz, 1H), 4.64 (d, J=15.6 Hz, 1H), 4.42-4.50 (m, 1H), 4.30-4.37(m, 1H), 2.98 (t, J=5.1 Hz, 2H), 2.44 (q, J=7.8 Hz, 2H), 2.12-2.19 (m,1H), 1.90-1.98 (m, 2H), 1.22 (t, J=7.4 Hz, 3H), 0.72 (t, J=7.4 Hz, 3H),MS: (ES) m/z calculated for C₃₀H₂₉F₄N₆O₄P [M+H]⁺ 645.2, found 645.6.

Example 51: Synthesis of((4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-5-fluoro-1H-indol-7-yl)methoxy)methyldihydrogen phosphate

Step a: To a stirred solution of(4-(2-(2,6-diethylphenyl)-5-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-5-fluoro-1H-indol-7-yl)methanol(140 mg, 0.25 mmol) in dichloromethane (4 mL) at room temperature wasadded diisopropylethylamine (77 mg, 0.74 mmol) and((chloromethoxy)methyl)benzene (77 mg, 0.49 mmol). The reaction mixturewas warmed to 50° C. and stirred for 4 h. After completion, the reactionmixture was cooled to room temperature. The mixture was diluted withwater and saturated aqueous NaHCO₃, extracted with dichloromethane,washed with brine and dried over Na₂SO₄. The solvent was removed underreduced pressure and the residue was purified by silica gelchromatography (10 to 100% EtOAc in hexanes) to give3-(7-(((benzyloxy)methoxy)methyl)-5-fluoro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine.¹H NMR (400 MHz, CDCl₃) δ 8.82 (br s, 1H), 8.47 (br s, 2H), 7.32-7.40(m, 4H), 7.12-7.25 (m, 3H), 6.85 (d, J=7.4 Hz, 1H), 6.63 (d, J=10.5 Hz,1H), 6.35 (t, J=3.1 Hz, 1H), 4.85-4.98 (m, 7H), 4.69 (d, J=16.8 Hz, 1H),4.65 (s, 2H), 4.40-4.50 (m, 1H), 4.25-4.35 (m, 1H), 3.0-3.12 (m, 1H),2.45-2.60 (m, 2H), 2.15-2.25 (m, 1H), 1.85-2.05 (m, 1H), 1.12 (t, J=7.4Hz, 3H), 0.73 (t, J=7.4 Hz, 3H). MS: (ES) m/z calculated forC₃₈H₃₆F₄N₆O₂ [M+H]⁺ 685.74, found 685.5.

Step b: To a stirred solution of3-(7-(((benzyloxy)methoxy)methyl)-5-fluoro-1H-indol-4-yl)-2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine(140 mg, 0.20 mmol) in dichloromethane (3 mL) was added trimethylsilyliodide (0.5 mL, 0.51 mmol). The reaction mixture was stirred for 2 h atroom temperature. After completion of the reaction, the solvent wasremoved in vacuo to give2-(2,6-diethylphenyl)-3-(5-fluoro-7-((iodomethoxy)methyl)-1H-indol-4-yl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine,which was used directly in the next step without further purification.

Step c: To a stirred suspension of phosphonic acid diisopropylethylamine salt (482 mg, 1.0 mmol) in MeCN (5 mL) and H₂O (5 drops) wasadded to2-(2,6-diethylphenyl)-3-(5-fluoro-7-((iodomethoxy)methyl)-1H-indol-4-yl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine(140 mg, 0.19 mmol). The reaction mixture was stirred for 2 h at roomtemperature. After completion of the reaction, the solvent was removedin vacuo and the mixture was diluted with water and extracted withEtOAc. The solvent was removed under reduced pressure and the residuewas purified by HPLC (MeCN/H₂O, with 0.1% NH₄CO₃) and lyophilized togive the ammonium salt of((4-(2-(2,6-diethylphenyl)-5-(5-[4,3-c]pyridin-3-yl)-5-fluoro-1H-indol-7-yl)methoxy)methyldihydrogen phosphate. The material was converted to sodium salt bydiluting with MeCN (0.6 mL)/H₂O (0.4 mL) and adding 0.1 M NaOH (213 μL,2 equiv.) and lyophilizing to dryness to give the disodium salt of((4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-5-fluoro-1H-indol-7-yl)methoxy)methyldihydrogen phosphate. ¹H NMR (400 MHz, D₂O) δ 8.07 (br s, 2H), 7.37 (brs, 1H), 7.07-7.15 (m, 2H), 6.79 (d, J=6.6 Hz, 1H), 6.21 (br s, 2H),4.87-4.95 (m, 2H), 4.76 (d, J=11.3 Hz, 1H), 4.15-4.25 (m, 2H), 3.60-3.85(m, 2H), 2.79 (br s, 2H), 2.00-2.25 (m, 4H), 1.65-1.85 (m, 2H), 0.93 (t,J=7.4 Hz, 3H), 0.35-0.50 (m, 3H), MS: (ES) m/z calculated forC₃₁H₃₁F₄N₆O₅P [M+H]⁺ 675.2, found 675.7.

Example 52: Synthesis of4-((4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indol-1-yl)methyl)-5-methyl-1,3-dioxol-2-one

Step a: To a stirred solution of4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indole(400 mg, 0.64 mmol) in THF (10 mL) was added 1 M LiHMDS solution in THF(1 mL, 1 mmol) at −78° C. After stirring for 30 min, a solution of4-(chloromethyl)-5-methyl-1,3-dioxol-2-one (113 mg, 0.76 mmol) in THF (3mL) was added at −78° C. The mixture was warmed up to room temperatureand stirred for 3 h. After completion, saturated NH₄Cl solution wasadded, and the mixture was extracted with EtOAc. The organic layers werecombined, dried over Na₂SO₄, filtered, and concentrated. The residue waspurified by silica gel column chromatography (10 to 30% EtOAc inhexanes) to give4-((4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indol-1-yl)methyl)-5-methyl-1,3-dioxol-2-one.¹H NMR (400 MHz, DMSO-d₆) δ 8.16 (d, J=8.2 Hz, 1H), 8.01 (d, J=8.2 Hz,1H), 7.97 (br s, 1H), 7.82 (d, J=3.5 Hz, 1H), 7.28 (t, J=7.8 Hz, 1H),7.13 (d, J=8.1 Hz, 1H), 7.08 (d, J=7.0 Hz, 1H), 6.84 (dd, J=8.06, 13.7Hz, 1H), 6.54 (dd, J=2.8, 3.6 Hz, 1H), 6.45 (dd, J=4.3, 8.2 Hz, 1H),4.99 (d, J=4.7 Hz, 1H), 4.45 (d, J=4.7 Hz, 1H), 4.15 (br s, 2H), 3.61(q, J=3.5 Hz, 1H), 2.33 (s, 3H), 2.20-2.25 (m, 2H), 2.05-2.15 (m, 2H),1.85-2.05 (m, 1H), 1.47 (s, 6H), 0.90 (t, J=7.4 Hz, 3H), 0.85 (t, J=7.4Hz, 3H). MS: (ES) m/z calculated for C₃₉H₃₅F₇N₄O₃ [M+H]⁺ 741.3, found741.2.

Example 53: Synthesis of (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-2,4,5,6-tetrahydro-6,6-dimethylpyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indole-1-carboxylate

To a 50 mL round bottom flask charged with4-(hydroxymethyl)-5-methyl-1,3-dioxol-2-one (0.5 g, 3.84 mmol) inanhydrous dichloromethane (6 mL) at −40° C. was added triethylamine(0.77 g, 7.62 mmol) followed by triphosgene (0.88 g, 4.58 mmol) dropwiseover 5 min. The reaction mixture was stirred at −40° C. for 1 h thenwarmed to room temperature for 1 h. After completion, the reactionmixture was diluted with H₂O and extracted with dichloromethane. Thecombined organic layers were dried over Na₂SO₄, filtered, andconcentrated in vacuo to give (5-methyl-2-oxo-1,3-dioxol-4-yl)methylcarbonochloridate which was used directly in the next step withoutfurther purification.

Example 53 was prepared similar to the procedure as described in Example52 using (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl-carbonochloridate and4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indole.¹H NMR (400 MHz, CD₃OD) δ 8.22 (d, J=6.6 Hz, 1H), 7.90-7.97 (m, 2H),7.81 (br s, 1H), 7.34 (t, J=7.4 Hz, 1H), 7.16 (d, J=7.4 Hz, 2H), 6.83(t, J=8.6 Hz, 1H), 6.60-6.75 (m, 2H), 5.24 (s, 2H), 4.23 (br s, 2H),3.71 (s, 2H), 2.25-2.38 (m, 4H), 2.24 (s, 3H), 1.57 (s, 6H), 1.03 (t,J=7.4 Hz, 6H). MS: (ES) m/z calculated for C₄₀H₃₅F₇N₄O₅ [M+H]⁺ 785.2,found 785.1.

Example 54: Synthesis of4-((4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indol-1-yl)methyl)-5-methyl-1,3-dioxol-2-one

Example 54 was prepared similar to the procedure as described in Example52 using 4-(chloromethyl)-5-methyl-1,3-dioxol-2-one and2-(2,6-diethylphenyl)-3-(6-fluoro-7-methoxy-1H-indol-4-yl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine¹H NMR (400 MHz, CD₃OD) δ 8.70 (br s, 2H), 7.86 (s, 1H), 7.28 (t, J=6.9Hz, 1H), 6.59 (br s, 1H), 6.40 (d, J=13.3 Hz, 1H), 5.02 (br s, 2H), 4.78(br s, 2H), 4.25-4.60 (m, 2H), 3.79 (s, 3H), 3.30 (br s, 2H), 2.89 (brs, 2H), 2.47 (s, 3H), 2.36 (br s, 4H), 0.67-1.12 (m, 6H). MS: (ES) m/zcalculated for C₃₅H₃₂F₄N₆O₄ [M+H]⁺ 677.24, found 677.2.

Example 55: Synthesis of (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indole-1-carboxylate

Example 55 was prepared similar to the procedure as described in Example52 using (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl chloroformate and2-(2,6-diethylphenyl)-3-(6-fluoro-7-methoxy-1H-indol-4-yl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine.¹H NMR (400 MHz, CD₃OD) δ 8.58 (br s, 2H), 7.78 (d, J=1.2 Hz, 1H), 7.32(t, J=1.2 Hz, 1H), 7.15-7.22 (m, 2H), 6.50-6.65 (m, 2H), 5.28 (s, 2H),4.38 (br s, 2H), 3.95 (s, 3H), 2.97 (br s, 2H), 2.30-2.40 (m, 6H), 2.26(s, 3H), 0.98-1.25 (m, 6H). MS: (ES) m/z calculated for C₃₆H₃₂F₄N₆O₆[M+H]⁺ 721.23, found 721.2.

Example 56: Synthesis of4-((4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-2,4,5,6-tetrahydro-6,6-dimethylpyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indole-1-carboxyloyloxy)methyl)phenyldihydrogen phosphate

Step a: To a 50 mL round bottom flask charged with4-(hydroxymethyl)phenol (0.27 g, 1.73 mmol), triethylamine (0.27 g, 1.73mmol), and anhydrous dichloromethane (6 mL) at 0° C. was addeddiethylphosphoryl chloride (0.54 g, 4.32 mmol) dropwise over 5 min. Thereaction mixture was stirred at room temperature for 16 h. Aftercompletion, the mixture was extracted with EtOAc. The organic layerswere combined, dried over Na₂SO₄, filtered, and concentrated. Theresidue was purified by silica gel column chromatography (10 to 80%EtOAc in hexanes) to give diethyl 4-(hydroxymethyl)-phenyl phosphate

To a stirred solution of diethyl 4-(hydroxymethyl)phenyl phosphate (0.27g, 1.73 mmol) and triethylamine in anhydrous dichloromethane (10 mL) at0° C. was added triphosgene (0.54 g, 4.32 mmol) slowly over 5 min. Thereaction mixture was stirred at room temperature for 1 h. Aftercompletion, the reaction mixture was diluted with H₂O and extracted withdichloromethane. The combined organic layers were dried over Na₂SO₄,filtered, and concentrated in vacuo to give4-((diethoxyphosphoryl)oxy)benzyl carbonochloridate which was useddirectly in the next step without further purification.

To a solution of4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-2,4,5,6-tetrahydro-6,6-dimethylpyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indole(150 mg, 0.23 mmol) in THF (4 mL) was added 1 M LiHMDS solution in THF(0.38 mL, 0.38 mmol) at −78° C. After stirring for 30 min, a solution of4-((diethoxyphosphoryl)oxy)benzyl carbonochloridate (153 mg, 0.47 mmol)in THF (2 mL) was added at −78° C. The reaction mixture was warmed toroom temperature and stirred for 2 h. After completion, saturatedaqueous NH₄Cl solution was added, extracted with EtOAc. The organiclayers were combined, dried over Na₂SO₄, filtered, and concentrated. Theresidue was purified by silica gel column chromatography (10 to 60%EtOAc in hexanes) to give4-((diethoxyphosphoryl)oxy)benzyl-4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indole-1-carboxylate.MS: (ES) m/z calculated for C₄₆H₄₆F₇N₄O₆P [M+H]⁺ 915.3, found 915.3.

Step b: To a stirred solution of4-((diethoxyphosphoryl)oxy)benzyl-4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indole-1-carboxylate(100 mg, 0.11 mmol) in dichloromethane (2.5 mL) was addedbromotrimethylsilane (83 mg, 0.55 mmol) at room temperature for 8 h.After completion, the mixture was concentrated to dryness and purifiedby HPLC (MeCN/H₂O, with 0.1% TFA) to give4-(phosphonooxy)benzyl-4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indole-1-carboxylate.¹H NMR (400 MHz, CD₃OD) δ 8.13 (s, 1H), 8.06 (s, 2H), 7.82 (d, J=3.5 Hz,1H), 7.46 (d, J=8.6 Hz, 2H), 7.35 (t, J=7.8 Hz, 1H), 7.22 (d, J=7.9 Hz,2H), 7.16 (d, J=7.8 Hz, 2H), 6.83 (dd, J=8.2, 12.1 Hz, 1H), 6.65-6.75(m, 2H), 5.40 (s, 2H), 4.72 (br s, 2H), 4.50 (br s, 2H), 2.15-2.30 (m,4H), 1.93 (s, 6H), 0.99 (t, J=7.4 Hz, 6H) MS: (ES) m/z calculated forC₄₂H₃₈F₇N₄O₆P [M+H]⁺ 859.24, found 859.2.

Example 57: Synthesis of4-(phosphonooxy)benzyl-4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)-pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indole-1-carboxylate

Step a: To a solution of 4-hydroxybenzaldehyde (3.0 g, 24.5 mmol) in 100mL of THF was added a 1.0 M solution of tBuOK in THF (27.04 mL, 27.04mmol). The mixture was heated to 70° C. and tetrabenzylphosphate wasadded (14.5 g, 26.95 mmol). After 1 h at 70° C., hexanes was added tothe mixture and the contents were filtered. The filtrate wasconcentrated in vacuo and the resulting residue was purified by silicagel column chromatography (0 to 100% EtOAc in hexanes) to producedibenzyl (4-formylphenyl)phosphate. MS: (ES) m/z calculated forC₂₁H₁₉O₅P [M+H]⁺ 383.1, found 383.2.

To a solution of dibenzyl (4-formylphenyl)phosphate (3.5 g, 9.16 mmol)in 50 mL of THF at −78° C. was added NaBH₄ (0.65 g, 18.3 mmol). Afterstirring at room temperature for 2 h, the mixture was quenched with H₂O.The organic and aqueous layers were separated and the aqueous layer wasextracted with EtOAc. The combined organic layers were dried with sodiumsulfate, filtered and concentrated in vacuo. The residue was purified bysilica gel column (0 to 100% EtOAc in hexanes) to providedibenzyl-4-(hydroxymethyl)phenyl)phosphate. MS: (ES) m/z calculated forC₂₁H₂₁O₅P [M+H]⁺ 385., found 385.1.

To a solution of dibenzyl-4-(hydroxymethyl)phenyl)phosphate (3.56 g,9.24 mmol) in 30 mL of THF at 0° C. was added diisopropylethylamine(2.98, 23.1 mmol) and triphosgene (3.0 g, 10.1 mmol). After stirring at0° C. for 1 h, the reaction was quenched with H₂O. The organic andaqueous layers were separated, and the aqueous layer was extracted withEtOAc. The organic layers were combined, dried with sodium sulfate,filtered and concentrated to form the crude chloroformate.

To a solution of2-(2,6-diethylphenyl)-3-(6-fluoro-7-methoxy-1H-indol-4-yl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine(250 mg, 0.442 mmol) in 1.2 mL of THF at 0° C. was added NaH (26 mg,1.05 mmol). After stirring at 0° C. for 30 min, a solution of the crudechloroformate formed above (247 mg, 0.553 mmol) in THF (2 mL) was addedto the mixture. The solution was stirred at 0° C. for 1 h then quenchedwith H₂O. The organic and aqueous layers were separated and the aqueouslayer was extracted with EtOAc. The organic layers were combined, driedwith sodium sulfate, filtered and concentrated in vacuo.

The residue was purified by silica gel column chromatography (0 to 50%EtOAc in hexanes) to give 4-((bis(benzyloxy)phosphoryl)oxy)benzyl4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indole-1-carboxylate.

Step b: To a solution of 4-((bis(benzyloxy)phosphoryl)oxy)benzyl4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indole-1-carboxylate(150 mg, 0.15 mmol) in 7 mL of THF was added 10% Pd/C (50 mg). Themixture was stirred under a H2 balloon for 1 h, then filtered throughCelite, concentrated and purified by HPLC (MeCN/H₂O, with 0.1% TFA) togive 4-(phosphonooxy)benzyl4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indole-1-carboxylate.¹H NMR (400 MHz, DMSO-d₆) δ 7.90 (br s, 1H), 6.99 (d, J=3.5 Hz, 1H),6.20-6.60 (m, 10H), 5.80 (d, J=3.5 Hz, 1H), 5.69 (d, J=12.5 Hz, 1H),4.53 (s, 2H), 3.94 (br s, 2H), 3.48 (br s, 2H), 3.0 (s, 3H), 2.08 (br s,2H), 1.68-1.95 (m, 2H), 0.98-1.45 (m, 6H), MS: (ES) m/z calculated forC₃₈H₃₅F₄N₆O₇P [M+H]⁺ 795.22, found 795.2.

Example 58: Synthesis of2-(4-(4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-2,4,5,6-tetrahydro-6,6-dimethylpyrrolo-[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indol-1-yl)-2-methyl-4-oxobutan-2-yl)-3,5-dimethylphenyldihydrogen phosphate

To a solution of3-(2-((bis(benzyloxy)phosphoryl)oxy)-4,6-dimethylphenyl)-3-methylbutanoicacid (1.0 g, 2.07 mmol) in anhydrous dichloromethane (10 mL) was addeddiisopropylethylamine followed by isobutyl chloroformate (298 mg, 2.49mmol) in dichloromethane (10 mL) at 0° C. dropwise over 5 min. Thereaction mixture was stirred at room temperature for 2 h. Aftercompletion of the reaction, the reaction mixture was diluted with H₂Oand extracted with dichloromethane. The combined organic layers weredried over Na₂SO₄, filtered, and concentrated in vacuo to give3-(2-((bis(benzyloxy)phosphoryl)oxy)-4,6-dimethylphenyl)-3-methylbutanoic(isobutyl carbonic) anhydride, which was used directly in the next stepwithout further purification.

To a solution of4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-(400 mg,0.63 mmol) in THF (10 mL) was added 1M LiHMDS solution in THF (1.01 mL,1.01 mmol) at −78° C. After stirring for 30 min, a solution of3-(2-((bis(benzyloxy)phosphoryl)oxy)-4,6-dimethylphenyl)-3-methylbutanoic(isobutyl carbonic) anhydride (0.46 g, 0.8 mmol) in THF (5 mL) was addedat −78° C. and stirred for 1 h. The mixture was warmed to roomtemperature and stirred for 2 h. After completion, saturated aqueousNH₄Cl solution was added, and the mixture was extracted with EtOAc. Theorganic layers were combined, dried over Na₂SO₄, filtered, andconcentrated. The residue was purified by silica gel columnchromatography (10 to 60% EtOAc in hexanes) to give dibenzyl(2-(4-(4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indol-1-yl)-2-methyl-4-oxobutan-2-yl)-3,5-dimethylphenyl)phosphate.

To a solution of the resulting phosphate (270 mg, 0.25 mmol) in ethanol(10 mL) was added 10% Pd/C (200 mg) at room temperature. The resultingmixture was stirred under a hydrogen (balloon) atmosphere for 1 h atroom temperature. The reaction mixture was filtered through Celite andthe filtrate was concentrated under reduced pressure to give2-(4-(4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-7-fluoro-1H-indol-1-yl)-2-methyl-4-oxobutan-2-yl)-3,5-dimethylphenyldihydrogen phosphate. ¹H NMR (400 MHz, DMSO-d₆) δ 12.22 (br s, 1H), 8.47(d, J=8.2 Hz, 1H), 8.35 (d, J=7.4 Hz, 1H), 8.30 (s, 1H), 8.23 (s, 1H),7.62 (t, J=8.2 Hz, 1H), 7.44 (d, J=7.0 Hz, 2H), 7.32 (br s, 1H), 7.15(t, J=10.9 Hz, 1H), 6.82-6.95 (m, 3H), 4.49 (br s, 2H), 3.85-4.05 (m,4H), 3.66 (br s, 1H), 2.72 (s, 3H), 2.42-2.60 (m, 4H), 2.38 (s, 3H),1.90 (s, 4H), 1.80 (s, 6H), 1.23 (t, J=7.4 Hz, 6H). MS: (ES) m/zcalculated for C₄₇H₄₈F₇N₄O₅P [M+H]⁺ 913.3, found 913.3.

Example 59: Synthesis of2-(4-(4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo-[4,3-c]pyridin-3-yl)-7-fluoro-1H-indol-1-yl)-2-methyl-4-oxobutan-2-yl)-3,5-dimethylphenyldihydrogen phosphate

To a solution of2-(2,6-diethylphenyl)-3-(6-fluoro-7-methoxy-1H-indol-4-yl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine(150 mg, 0.27 mmol) in THF (5 mL) was added 1M LiHMDS in THF (0.43 mL,0.43 mmol) at −78° C. After stirring for 30 min, a solution of3-(2-((bis(benzyloxy)phosphoryl)oxy)-4,6-dimethylphenyl)-3-methylbutanoic(isobutyl carbonic) anhydride (193 mg, 0.33 mmol) in THF (2.5 mL) wasadded at −78° C. and stirred for 1 h. The mixture was warmed to roomtemperature and stirred for 2 h. After completion of, saturated NH₄Clsolution was added, and the mixture was extracted with EtOAc. Theorganic layers were combined, dried over Na₂SO₄, filtered, andconcentrated. The residue was purified by silica gel columnchromatography (10 to 40% EtOAc in hexanes) to give dibenzyl(2-(4-(4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indol-1-yl)-2-methyl-4-oxobutan-2-yl)-3,5-dimethylphenyl)phosphate.

To a solution of the resulting phosphate (120 mg, 0.12 mmol) in ethanol(5 mL) was added 10% Pd/C (100 mg) at room temperature. The resultingmixture was stirred under a hydrogen (balloon) atmosphere for 1 h atroom temperature. The reaction mixture was filtered through Celite andthe filtrate was concentrated under reduced pressure to give2-(4-(4-(2-(2,6-diethylphenyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)-6-fluoro-7-methoxy-1H-indol-1-yl)-2-methyl-4-oxobutan-2-yl)-3,5-dimethylphenyldihydrogen phosphate. ¹H NMR (400 MHz, DMSO-d₆) δ 8.74 (br s, 2H), 7.89(d, J=1.2 Hz, 1H), 7.30-7.38 (m, 1H), 7.21 (br s, 2H), 7.07 (d, J=6.2Hz, 2H), 6.96 (s, 1H), 6.64 (s, 1H), 6.54 (s, 1H), 6.46-6.50 (m, 2H),4.76 (bs, 2H), 4.25-4.45 (m, 2H), 3.72 (s, 6H), 2.91 (br s, 2H), 2.46(br s, 5H), 2.14 (s, 3H), 1.65-2.05 (m, 4H), 0.80-1.20 (m, 6H). MS: (ES)m/z calculated for C₄₃H₄₅F₄N₆O₆P [M+H]⁺ 849.31, found 849.2.

Example 60: Synthesis of (4-phosphonooxyphenyl)methylN-((4-(5-((2,4-bis(trifluoromethyl)-phenyl)methyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-4H-pyrrolo[3,4-c]pyrazol-3-yl)-2,5-difluoro-phenyl)carbamoyl)carbamate

Step a: To a solution of dibenzyl-4-(hydroxymethyl)phenyl)phosphate(3.56 g, 9.24 mmol) in 2.4 mL of THF at 0° C. was addeddiisopropylethylamine (2.98, 23.1 mmol) and triphosgene (3.0 g, 10.1mmol). After stirring at 0° C. for 1 h, NH₄OH (5.0 mL, 41 mmol) wasadded. The mixture was stirred at room temperature for 16 h thenconcentrated in vacuo and the resultant residue was purified by silicagel column chromatography (20 to 80% EtOAc in hexanes) to give4-((bis(benzyloxy)phosphoryl)oxy)benzyl carbamate. MS: (ES) m/zcalculated for C₂₂H₂₂NO₆P [M+H]⁺ 428.1, found 428.1.

To a solution of 4-((bis(benzyloxy)phosphoryl)oxy)benzyl carbamate (700mg, 1.63 mmol) in dichloromethane (12 mL) at 0° C. was added oxalylchloride (0.3 g, 2.45 mmol). After stirring at 0° C. for 1 h, themixture was heated at 50° C. for 16 h then concentrated in vacuo. Theresidue was dissolved in THF (2 mL) and added to a solution of4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-2,5-difluoroaniline(150 mg, 0.16 mmol) in THF (2 mL). The mixture was stirred at roomtemperature for 5 h then concentrated in vacuo. The residue was purifiedby silica gel column chromatography (0 to 100% EtOAc in hexanes) to give(4-dibenzyloxyphosphoryloxy-3-phenyl)methylN-((4-(5-((2,4-bis(trifluoromethyl)phenyl)methyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-4H-pyrrolo[3,4-c]pyrazol-3-yl)-2,5-difluorophenyl)carbamoyl)carbamate.

Step b: To a solution of 4-dibenzyloxyphosphoryloxy-3-phenyl)methylN-((4-(5-((2,4-bis(trifluoromethyl)phenyl)methyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-4H-pyrrolo[3,4-c]pyrazol-3-yl)-2,5-difluorophenyl)carbamoyl)carbamate(150 mg, 0.14 mmol) in dichloromethane (2 mL) was added dropwise 1:1mixture of TFA:CH₂Cl₂ (2 mL) and H₂O (0.4 mL) The mixture was heated at50° C. for 48 h, then concentrated in vacuo. The residue was purified onHPLC (MeCN/H₂O, with 0.1% TFA) to yield (4-phosphonooxyphenyl)methylN-((4-(5-((2,4-bis(trifluoromethyl)phenyl)methyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-4H-pyrrolo[3,4-c]pyrazol-3-yl)-2,5-difluoro-phenyl)carbamoyl)carbamate.¹H NMR (400 MHz, DMSO-d₆) δ 10.78 (s, 1H), 10.15 (s, 1H), 8.14 (d, J=8.4Hz, 1H), 7.95-8.08 (m, 3H), 7.35-7.45 (m, 3H), 7.08-7.25 (m, 4H), 6.53(dd, J=6.7, 11.7 Hz, 1H), 5.11 (s, 2H), 4.12 (br s, 2H), 3.65 (br s,2H), 2.05-2.25 (m, 4H), 1.43 (s, 6H), 0.96 (t, J=7.4 Hz, 6H). MS: (ES)m/z calculated for C₄₁H₃₈F₈N₅O₇P [M+H]⁺ 896.2, found 896.2.

Example 61: 4-(benzyloxy(hydroxy)phosphoryl)oxyphenyl)methylN-((4-(5-((2,4-bis(trifluoromethyl)phenyl)methyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-4H-pyrrolo[3,4-c]pyrazol-3-yl)-2,5-difluoro-phenyl)carbamoyl)carbamate

The step b of Example 60 also gave Example 61. ¹H NMR (400 MHz, DMSO-d₆)δ 10.79 (s, 1H), 10.14 (br s, 1H), 8.14 (d, J=7.0 Hz, 1H), 7.85-8.10 (m,3H), 7.25-7.40 (m, 7H)), 7.20 (d, J=22.2 Hz, 2H), 7.14 (d, J=9.0 Hz,2H), 6.53 (dd, J=6.7, 11.4 Hz, 1H), 5.13 (s, 2H), 4.99 (d, J=7.9 Hz,2H), 4.12 (br s, 2H), 3.65 (br s, 2H), 2.10-2.25 (m, 4H), 1.43 (s, 6H),0.96 (t, J=7.4 Hz, 6H). MS: (ES) m/z calculated for C₄₈H₄₄F₈N₅O₇P [M+H]⁺986.3, found 986.3.

Example 62: Synthesis ofN-((4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-2,5-difluorophenyl)carbamoyl)-2-(dimethylamino)acetamide

To a stirred solution of4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-2,5-difluoroaniline(400 mg, 0.64 mmol) in THF (5 mL) was added 2-chloroacetyl isocyanate atroom temperature. After and stirring for 16 h, the mixture was quenchedwith H₂O and extracted with EtOAc. The combined organic layers weredried with sodium sulfate, filtered and concentrated in vacuo to giveN-((4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-2,5-difluorophenyl)carbamoyl)-2-chloroacetamide.

To a solution ofN-((4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-2,5-difluorophenyl)carbamoyl)-2-chloroacetamideform above (125 mg, 0.17 mmol) in THF (5 mL) was added dimethylamine(0.35 mL, 0.34 mmol) at room temperature. The reaction mixture wasstirred for 16 h then concentrated in vacuo. The residue was purified byHPLC (H₂O/ACN, 0.1% TFA) to give 5-difluorophenyl)carbamoyl)-2-(400 MHz,DMSO-d₆) δ 11.3 (br s, 1H), 10.3 (br s, 1H), 9.85 (br s, 1H), 7.90-8.25(m, 4H), 7.40-7.45 (m, 1H), 7.20-7.28 (m, 2H), 6.55-6.65 (m, 1H),4.10-4.35 (m, 3H), 3.70 (br s, 2H), 2.83 (s, 6H), 2.17 (q, J=8.2 Hz,4H), 1.45 (s, 6H), 0.95 (t, J=7.4 Hz, 6H). MS: (ES) m/z calculated forC₃₇H₃₈F₈N₆O₂P [M+H]⁺ 751.3, found 751.2.

Example 63: Synthesis of1-(4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-2,5-difluorophenyl)-3-(pyrrolidin-1-ylmethyl)urea

Step a: To a stirred solution of 2-hydroxyacetic acid (5.0 g, 65.7 mmol)in dichloromethane (100 mL) at 0° C., were added imidazole (11.7 g,164.3 mmol) and TBSCl (19.7 g, 131.4 mmol). The reaction mixture wasstirred for 16 h at room temperature. The reaction mixture was quenchedwith dropwise addition of saturated aqueous NaHCO₃ and extracted withdichloromethane. The organic layer was washed with brine, dried overNa₂SO₄, filtered and concentrated. The crude material was used directlyin the next step without further purification.

To a solution of 2-tert-butyldimethylsilyloxy acetic acid (10.0 g, 32.6mmol) in 50 mL of dichlromethane at 0° C. was added oxalylchloride (8.23g, 65.3 mmol). The reaction mixture was stirred for 3 h at roomtemperature, After completion of the reaction, the solvent was removedunder reduced pressure and dried under vacuum. The crude material wasused directly in the next step.

To a stirred solution of 2-tert-butyldimethylsilyloxy acetyl chloride(5.0 g, 15.4 mmol) in 1:1 mixture of Acetone:H₂O (30 mL) was added NaN₃(2.5 g, 38.5 mmol) at room temperature and stirred for 2 h. Aftercompletion, the solvent was removed under reduced pressure and themixture was extracted with EtOAc. The combined organic layers were driedwith sodium sulfate, filtered and concentrated in vacuo to give2-tert-butyldimethylsilyloxy acetyl azide. The azide (3.2 g 1.63 mmol)was dissolved in 20 mL of chloroform at room temperature and the mixturewas heated at 80° C. for 2 h. The solvent was removed in vacuo and useddirectly in the next step.

To a solution of tert-butyl(isocyanatomethoxy)dimethylsilane (0.56 g)was dissolved in THF (5 mL) and added to a solution of4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-2,5-difluoroaniline(1.25 g, 2.0 mmol) in THF (10 mL). The mixture was stirred at roomtemperature for 5 h then concentrated in vacuo. The residue was purifiedby silica gel column chromatography (0 to 100% EtOAc in hexanes, with 1%Et₃N) to give1-(4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-2,5-difluorophenyl)-3-(((tert-butyldimethylsilyl)oxy)methyl)urea.MS: (ES) m/z calculated for C₄₀H₄₇F₈N₅O₂Si [M+H]⁺ 810.3, found 810.1.

Step b: To a solution of1-(4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-2,5-difluorophenyl)-3-(((tert-butyldimethylsilyl)oxy)methyl)urea(150 mg, 0.19 mmol) in dichloromethane (3 mL) was added dropwise TMSBr(84 mg, 0.55 mmol) at 0° C. The mixture was stirred at room temperaturefor 1 h, concentrated in vacuo. This material was dissolved indichloromethane (4.0 mL) and pyrrolidine (65 mg, 0.92 mmol) was added.The mixture was stirred at room temperature for 4 h then concentrated invacuo. The residue was purified by HPLC (MeCN/H₂O, with 0.1% TFA) togive1-(4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-2,5-difluorophenyl)-3-(pyrrolidin-1-ylmethyl)urea.¹H NMR (400 MHz, CD₃OD) δ 8.19 (d, J=5.9, Hz, 1H), 8.00-8.10 (m, 3H),7.42-7.48 (m, 1H), 7.20-7.35 (m, 2H), 6.45 (dd, J=6.6, 11.7 Hz, 1H),4.61 (s, 2H), 4.35-4.55 (m, 2H), 3.85-4.20 (m, 2H), 3.45-3.55 (m, 2H),3.10-3.35 (m, 3H), 2.25 (q, J=7.4 Hz, 4H), 1.90-2.18 (m, 5H), 1.65 (s,6H), 1.06 (t, J=7.8 Hz, 6H). MS: (ES) m/z calculated for C₃₈H₄₀F₈N₆O[M+H]⁺ 749.3, found 749.2.

Example 64: Synthesis of1-(4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-2,5-difluorophenyl)-3-(hydroxymethyl)urea

Step a: To a solution of1-(4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-2,5-difluorophenyl)-3-(((tert-butyldimethylsilyl)oxy)methyl)urea(200 mg, 0.24 mmol) in dichloromethane (1.4 mL) was added dropwise TMSBr(0.11 mL, 0.86 mmol). The mixture was stirred at room temperature for 1h, then concentrated in vacuo and purified by HPLC (MeCN/H₂O, with 0.1%TFA) to give1-(4-(5-(2,4-bis(trifluoromethyl)benzyl)-2-(2,6-diethylphenyl)-6,6-dimethyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-2,5-difluorophenyl)-3-(hydroxymethyl)urea.¹H NMR (400 MHz, CD₃OD) δ 8.00-8.25 (m, 4H), 7.42-7.50 (m, 1H),7.25-7.30 (m, 2H), 6.36-6.45 (m, 1H), 4.75 (br s, 1H), 4.40-4.70 (m,5H), 2.25 (q, J=7.4 Hz, 4H), 1.80-1.95 (m, 6H), 1.04 (t, J=3.5 Hz, 6H).MS: (ES) m/z calculated for C₃₄H₃₃F₈N₅O₂ [M+H]⁺ 696.3, found 696.3.

Example 65

This example illustrates the evaluation of the biological activityassociated with specific compounds of the invention.

Materials and Methods

Cells

C5a Receptor Expressing Cells

U937 Cells

U937 cells are a monocytic cell line which express C5aR, and areavailable from ATCC (VA). These cells were cultured as a suspension inRPMI-1640 medium supplemented with 2 mM L-glutamine, 1.5 g/L sodiumbicarbonate, 4.5 g/L glucose, 10 mM HEPES, 1 mM sodium pyruvate, and 10%FBS. Cells were grown under 5% CO₂/95% air, 100% humidity at 37° C. andsubculture twice weekly at 1:6 (cells were cultured at a density rangeof 1×10⁵ to 2×10⁶ cells/mL) and harvested at 1×10⁶ cells/mL. Prior toassay, cells are treated overnight with 0.5 mM of cyclic AMP (Sigma, OH)and washed once prior to use. cAMP treated U937 cells can be used inC5aR ligand binding and functional assays.

Isolated Human Neutrophils

Optionally, human or murine neutrophils can be used to assay forcompound activity. Neutrophils may be isolated from fresh human bloodusing density separation and centrifigation. Briefly, whole blood isincubated with equal parts 3% dextran and allowed to separate for 45minutes. After separation, the top layer is layered on top of 15 mls ofFicoll (15 mls of Ficoll for every 30 mls of blood suspension) andcentrifuged for 30 minutes at 400×g with no brake. The pellet at thebottom of the tube is then isolated and resuspended into PharmLyse RBCLysis Buffer (BD Biosciences, San Jose, Calif.) after which the sampleis again centrifuged for 10 minutes at 400×g with brake. The remainingcell pellet is resuspended as appropriate and consists of isolatedneutrophils.

Assays

Inhibition of C5aR Ligand Binding

cAMP treated U937 cells expressing C5aR were centrifuged and resuspendedin assay buffer (20 mM HEPES pH 7.1, 140 mM NaCl, 1 mM CaCl₂, 5 mMMgCl₂, and with 0.1% bovine serum albumin) to a concentration of 3×10⁶cells/mL. Binding assays were set up as follows. 0.1 mL of cells wasadded to the assay plates containing 5 μL of the compound, giving afinal concentration of ˜2-10 μM each compound for screening (or part ofa dose response for compound IC₅₀ determinations). Then 0.1 mL of ¹²⁵Ilabeled C5a (obtained from Perkin Elmer Life Sciences, Boston, Mass.)diluted in assay buffer to a final concentration of ˜50 μM,yielding˜30,000 cpm per well, was added, the plates sealed and incubatedfor approximately 3 hours at 4° C. on a shaker platform. Reactions wereaspirated onto GF/B glass filters pre-soaked in 0.3% polyethyleneimine(PEI) solution, on a vacuum cell harvester (Packard Instruments;Meriden, Conn.). Scintillation fluid (40 μl; Microscint 20, PackardInstruments) was added to each well, the plates were sealed andradioactivity measured in a Topcount scintillation counter (PackardInstruments). Control wells containing either diluent only (for totalcounts) or excess C5a (1 μg/mL, for non-specific binding) were used tocalculate the percent of total inhibition for compound. The computerprogram Prism from GraphPad, Inc. (San Diego, Ca) was used to calculateIC₅₀ values. IC₅₀ values are those concentrations required to reduce thebinding of radiolabeled C5a to the receptor by 50%. (For furtherdescriptions of ligand binding and other functional assays, seeDairaghi, et al., J. Biol. Chem. 274:21569-21574 (1999), Penfold, etal., Proc. Natl. Acad. Sci. USA. 96:9839-9844 (1999), and Dairaghi, etal., J. Biol. Chem. 272:28206-28209 (1997)).

Calcium Mobilization

Optionally, compounds may be further assayed for their ability toinhibit calcium flux in cells. To detect the release of intracellularstores of calcium, cells (e.g., cAMP stimulated U937 or neutrophils) areincubated with 3 μM of INDO-1AM dye (Molecular Probes; Eugene, Oreg.) incell media for 45 minutes at room temperature and washed with phosphatebuffered saline (PBS). After INDO-1AM loading, the cells are resuspendedin flux buffer (Hank's balanced salt solution (HBSS) and 1% FBS).Calcium mobilization is measured using a Photon Technology Internationalspectrophotometer (Photon Technology International; New Jersey) withexcitation at 350 nm and dual simultaneous recording of fluorescenceemission at 400 nm and 490 nm. Relative intracellular calcium levels areexpressed as the 400 nm/490 nm emission ratio. Experiments are performedat 37° C. with constant mixing in cuvettes each containing 10⁶ cells in2 mL of flux buffer. The chemokine ligands may be used over a range from1 to 100 nM. The emission ratio is plotted over time (typically 2-3minutes). Candidate ligand blocking compounds (up to 10 μM) are added at10 seconds, followed by chemokines at 60 seconds (i.e., C5a; R&DSystems; Minneapolis, Minn.) and control chemokine (i.e., SDF-1α; R&DSystems; Minneapolis, Minn.) at 150 seconds.

Chemotaxis Assays

Optionally, compounds may be further assayed for their ability toinhibit chemotaxis in cells. Chemotaxis assays are performed using 5 μmpore polycarbonate, polyvinylpyrrolidone-coated filters in 96-wellchemotaxis chambers (Neuroprobe; Gaithersburg, Md.) using chemotaxisbuffer (Hank's balanced salt solution (HMS) and 1% FBS). C5aR ligands(i.e., C5a, R&D Systems; Minneapolis, Minn.) are use to evaluatecompound mediated inhibition of C5aR mediated migration. Otherchemokines (i.e., SDF-1α; R&D Systems; Minneapolis, Minn.) are used asspecificity controls. The lower chamber is loaded with 29 μl ofchemokine (i.e., 0.03 nM C5a) and varying amounts of compound; the topchamber contains 100,000 U937 or neutrophil cells in 20 μl. The chambersare incubated 1.5 hours at 37° C., and the number of cells in the lowerchamber quantified either by direct cell counts in five high poweredfields per well or by the CyQuant assay (Molecular Probes), afluorescent dye method that measures nucleic acid content andmicroscopic observation.

Identification of Inhibitors of C5aR Assay

To evaluate small organic molecules that prevent the C5a receptor frombinding ligand, an assay was employed that detected radioactive ligand(i.e, C5a) binding to cells expressing C5aR on the cell surface (forexample, cAMP stimulated U937 cells or isolated human neutrophils). Forcompounds that inhibited binding, whether competitive or not, fewerradioactive counts are observed when compared to uninhibited controls.

Equal numbers of cells were added to each well in the plate. The cellswere then incubated with radiolabeled C5a. Unbound ligand was removed bywashing the cells, and bound ligand was determined by quantifyingradioactive counts. Cells that were incubated without any organiccompound gave total counts; non-specific binding was determined byincubating the cells with unlabeled ligand and labeled ligand. Percentinhibition was determined by the equation:

%  inhibition = (1 − [(sample  cpm) − (nonspecific  cpm)]/  [(total  cpm) − (nonspecific  cpm)] × 100.Dose Response Curves

To ascertain a candidate compound's affinity for C5aR as well as confirmits ability to inhibit ligand binding, inhibitory activity was titeredover a 1×10⁻¹⁰ to 1×10⁻⁴ M range of compound concentrations. In theassay, the amount of compound was varied; while cell number and ligandconcentration were held constant.

In Vivo Efficacy Models

The compounds of interest can be evaluated for potential efficacy intreating a C5a mediated conditions by determining the efficacy of thecompound in an animal model. In addition to the models described below,other suitable animal models for studying the compound of interest canbe found in Mizuno, M. et al., Expert Opin. Investig. Drugs (2005),14(7), 807-821, which is incorporated herein by reference in itsentirety.

Models of C5a Induced Leukopenia C5a Induced Leukopenia in a Human C5aRKnock-in Mouse Model

To study the efficacy of compounds of the instant invention in an animalmodel, a recombinant mouse can be created using standard techniques,wherein the genetic sequence coding for the mouse C5aR is replaced withsequence coding for the human C5aR, to create a hC5aR-KI mouse. In thismouse, administration of hC5a leads to upregulation of adhesionmolecules on blood vessel walls which bind blood leukocytes,sequestering them from the blood stream. Animals are administered 20ug/kg of hC5a and 1 minute later leukocytes are quantified in peripheralblood by standard techniques. Pretreatment of mice with varying doses ofthe present compounds can almost completely block the hC5a inducedleukopenia.

C5a Induced Leukopenia in a Cynomolgus Model

To study the efficacy of compounds of the instant invention in anon-human primate model model, C5a induced leucopenia is studied in acynomolgus model. In this model administration of hC5a leads toupregulation of adhesion molecules on blood vessel walls which bindblood leukocytes, hence sequestering them from the blood stream. Animalsare administered 10 ug/kg of hC5a and 1 minute later leukocytes arequantified in peripheral blood.

Mouse Model of ANCA Induced Vasculitis

On day 0 hC5aR-KI mice are intraveneously injected with 50 mg/kgpurified antibodiy to myeloperoxidase (Xiao et al, J. Clin. Invest. 110:955-963 (2002)). Mice are further dosed with oral daily doses ofcompounds of the invention or vehicle for seven days, then mice aresacrificed and kidneys collected for histological examination. Analysisof kidney sections can show significantly reduced number and severity ofcrescentic and necrotic lesions in the glomeruli when compared tovehicle treated animals.

Mouse Model of Choroidal Neovascularization

To study the efficacy of compounds of the instant invention in treatmentof age related macular degeneration (AMD) the bruch membrane in the eyesof hC5aR-KI mice are ruptured by laser photocoagulation (Nozika et al,PNAS 103: 2328-2333 (2006). Mice are treated with vehicle or a dailyoral or appropriate intra-vitreal dose of a compound of the inventionfor one to two weeks. Repair of laser induced damage andneovascularization are assessed by histology and angiography.

Rheumatoid Arthritis Models Rabbit Model of Destructive JointInflammation

To study the effects of candidate compounds on inhibiting theinflammatory response of rabbits to an intra-articular injection of thebacterial membrane component lipopolysaccharide (LPS), a rabbit model ofdestructive joint inflammation is used. This study design mimics thedestructive joint inflammation seen in arthritis. Intra-articularinjection of LPS causes an acute inflammatory response characterized bythe release of cytokines and chemokines, many of which have beenidentified in rheumatoid arthritic joints. Marked increases inleukocytes occur in synovial fluid and in synovium in response toelevation of these chemotactic mediators. Selective antagonists ofchemokine receptors have shown efficacy in this model (see Podolin, etal, J. Immunol. 169(11):6435-6444 (2002)).

A rabbit LPS study is conducted essentially as described in Podolin, etal. ibid., female New Zealand rabbits (approximately 2 kilograms) aretreated intra-articularly in one knee with LPS (10 ng) together witheither vehicle only (phosphate buffered saline with 1% DMSO) or withaddition of candidate compound (dose 1=50 μM or dose 2=100 μM) in atotal volume of 1.0 mL. Sixteen hours after the LPS injection, knees arelavaged and cells counts are performed. Beneficial effects of treatmentwere determined by histopathologic evaluation of synovial inflammation.Inflammation scores are used for the histopathologic evaluation:1—minimal, 2—mild, 3—moderate, 4—moderate-marked.

Evaluation of a Compound in a Rat Model of Collagen Induced Arthritis

A 17 day developing type II collagen arthritis study is conducted toevaluate the effects of a candidate compound on arthritis inducedclinical ankle swelling. Rat collagen arthritis is an experimental modelof polyarthritis that has been widely used for preclinical testing ofnumerous anti-arthritic agents (see Trentham, et al., J. Exp. Med.146(3):857-868 (1977), Bendele, et al., Toxicologic Pathol. 27:134-142(1999), Bendele, et al., Arthritis Rheum. 42:498-506 (1999)). Thehallmarks of this model are reliable onset and progression of robust,easily measurable polyarticular inflammation, marked cartilagedestruction in association with pannus formation and mild to moderatebone resorption and periosteal bone proliferation.

Female Lewis rats (approximately 0.2 kilograms) are anesthetized withisoflurane and injected with Freund's Incomplete Adjuvant containing 2mg/mL bovine type II collagen at the base of the tail and two sites onthe back on days 0 and 6 of this 17 day study. A candidate compound isdosed daily in a sub-cutaneous manner from day 0 till day 17 at aefficacious dose. Caliper measurements of the ankle joint diameter weretaken, and reducing joint swelling is taken as a measure of efficacy.

Rat Model of Sepsis

To study the effect of compounds of interest on inhibiting thegeneralized inflammatory response that is associated with a sepsis likedisease, the Cecal Ligation and Puncture (CLP) rat model of sepsis isused. A Rat CLP study is conducted essentially as described in FujimuraN, et al. (American Journal Respiratory Critical Care Medicine 2000;161: 440-446). Briefly described here, Wistar Albino Rats of both sexesweighing between 200-250 g are fasted for twelve hours prior toexperiments. Animals are kept on normal 12 hour light and dark cyclesand fed standard rat chow up until 12 hours prior to experiment. Thenanimals are split into four groups; (i) two sham operation groups and(ii) two CLP groups. Each of these two groups (i.e., (i) and (ii)) issplit into vehicle control group and test compound group. Sepsis isinduced by the CLP method. Under brief anesthesia a midline laparotomyis made using minimal dissection and the cecum is ligated just below theileocaecal valve with 3-0 silk, so the intestinal continuity ismaintained. The antimesinteric surface of the cecum is perforated withan 18 gauge needle at two locations 1 cm apart and the cecum is gentlysqueezed until fecal matter is extruded. The bowel is then returned tothe abdomen and the incision is closed. At the end of the operation, allrats are resuscitated with saline, 3 ml/100 g body weight, givensubcutaneously. Postoperatively, the rats are deprived of food, but havefree access to water for the next 16 hours until they are sacrificed.The sham operated groups are given a laparotomy and the cecum ismanipulated but not ligated or perforated. Beneficial effects oftreatment are measured by histopathological scoring of tissues andorgans as well as measurement of several key indicators of hepaticfunction, renal function, and lipid peroxidation. To test for hepaticfunction aspartate transaminase (AST) and alanine transaminase (ALT) aremeasured. Blood urea nitrogen and creatinine concentrations are studiedto assess renal function. Pro-inflammatory cytokines such as TNF-alphaand IL-1 beta are also assayed by ELISA for serum levels.

Mouse SLE Model of Experimental Lupus Nephritis.

To study the effect of compounds of interest on a Systemic LupusErythematosus (SLE), the MRL/lpr murine SLE model is used. TheMRL/Mp-Tmfrsf6^(lPr/lPr) strain (MRL/lpr) is a commonly used mouse modelof human SLE. To test compounds efficacy in this model male MRL/lpr miceare equally divided between control and C5aR antagonists groups at 13weeks of age. Then over the next 6 weeks compound or vehicle isadministered to the animals via osmotic pumps to maintain coverage andminimize stress effects on the animals. Serum and urine samples arecollected bi-weekly during the six weeks of disease onset andprogression. In a minority of these mice glomerulosclerosis developsleading to the death of the animal from renal failure. Followingmortality as an indicator of renal failure is one of the measuredcriteria and successful treatment will usually result in a delay in theonset of sudden death among the test groups. In addition, the presenceand magnitude of renal disease may also be monitored continuously withblood urea nitrogen (BUN) and albuminuria measurements. Tissues andorgans were also harvested at 19 weeks and subjected to histopathologyand immunohistochemistry and scored based on tissue damage and cellularinfiltration.

Rat Model of COPD

Smoke induced airway inflammation in rodent models may be used to assessefficacy of compounds in Chronic Obstructive Pulmonary Disease (COPD).Selective antagonists of chemokines have shown efficacy in this model(see, Stevenson, et al., Am. J. Physiol Lung Cell Mol Physiol. 288L514-L522, (2005)). An acute rat model of COPD is conducted as describedby Stevenson et al. A compound of interest is administered eithersystemically via oral or IV dosing; or locally with nebulized compound.Male Sprague-Dawley rats (350-400 g) are placed in Perspex chambers andexposed to cigarette smoke drawn in via a pump (50 mL every 30 secondswith fresh air in between). Rats are exposed for a total period of 32minutes. Rats are sacrificed up to 7 days after initial exposure. Anybeneficial effects of treatment are assessed by a decrease inflammatorycell infiltrate, decreases in chemokine and cytokine levels.

In a chronic model, mice or rats are exposed to daily tobacco smokeexposures for up to 12 months. Compound is administered systemically viaonce daily oral dosing, or potentially locally via nebulized compound.In addition to the inflammation observed with the acute model (Stevensenet al.), animals may also exhibit other pathologies similar to that seenin human COPD such as emphysema (as indicated by increased mean linearintercept) as well as altered lung chemistry (see Martorana et al, Am.J. Respir. Crit Care Med. 172(7): 848-53.

Mouse EAE Model of Multiple Sclerosis

Experimental autoimmune encephalomyelitis (EAE) is a model of humanmultiple sclerosis. Variations of the model have been published, and arewell known in the field. In a typical protocol, C57BL/6 (Charles RiverLaboratories) mice are used for the EAE model. Mice are immunized with200 ug myelin oligodendrocyte glycoprotein (MOG) 35-55 (PeptideInternational) emulsified in Complete Freund's Adjuvant (CFA) containing4 mg/ml Mycobacterium tuberculosis (Sigma-Aldrich) s.c. on day 0. Inaddition, on day 0 and day 2 animals are given 200 ng of pertussis toxin(Calbiochem) i.v. Clinical scoring is based on a scale of 0-5: 0, nosigns of disease; 1, flaccid tail; 2, hind limb weakness; 3, hind limbparalysis; 4, forelimb weakness or paralysis; 5, moribund. Dosing of thecompounds of interest to be assessed can be initiated on day 0(prophylactic) or day 7 (therapeutic, when histological evidence ofdisease is present but few animals are presenting clinical signs) anddosed once or more per day at concentrations appropriate for theiractivity and pharmacokinetic properties, e.g. 100 mg/kg s.c. Efficacy ofcompounds can be assessed by comparisons of severity (maximum meanclinical score in presence of compound compared to vehicle), or bymeasuring a decrease in the number of macrophages (F4/80 positive)isolated from spinal cords. Spinal cord mononuclear cells can beisolated via discontinuous Percoll-gradient. Cells can be stained usingrat anti-mouse F4/80-PE or rat IgG2b-PE (Caltag Laboratories) andquantitated by FACS analysis using 10 ul of Polybeads per sample(Polysciences).

Mouse Model of Kidney Transplantation

Transplantation models can be performed in mice, for instance a model ofallogenic kidney transplant from C57BL/6 to BALB/c mice is described inFaikah Gueler et al, JASN Express, Aug. 27, 2008. Briefly, mice areanesthetized and the left donor kidney attached to a cuff of the aortaand the renal vein with a small caval cuff, and the ureters removed enblock. After left nephrectomy of the recipient, the vascular cuffs areanastomosed to the recipient abdominal aorta and vena cava,respectively, below the level of the native renal vessels. The ureter isdirectly anastomosed into the bladder. Cold ischemia time is 60 min, andwarm ischemia time is 30 min. The right native kidney can be removed atthe time of allograft transplantation or at posttransplantation day 4for long-term survival studies. General physical condition of the miceis monitored for evidence of rejection. Compound treatment of animalscan be started before surgery or immediately after transplantation, egby sub cut injection once daily. Mice are studied for renal function andsurvival. Serum creatinine levels are measured by an automated method(Beckman Analyzer, Krefeld, Germany).

Mouse Model of Ischemia/Reperfusion

A mouse model of ischemia/reperfusion injury can be performed asdescribed by Xiufen Zheng et al, Am. J. Pathol, Vol 173:4, October,2008. Briefly, CD1 mice aged 6-8 weeks are anesthetized and placed on aheating pad to maintain warmth during surgery. Following abdominalincisions, renal pedicles are bluntly dissected and a microvascularclamp placed on the left renal pedicle for 25-30 minutes. Followingischemia the clamps are removed along with the right kidney, incisionssutured, and the animals allowed to recover. Blood is collected forserum creatinine and BUN analysis as an indicator of kidney health.Alternatively animal survival is monitored over time. Compound can beadministered to animals before and/or after the surgery and the effectson serum creatinine, BUN or animal survival used as indicators ofcompound efficacy.

Mouse Model of Tumor Growth

C57BL/6 mice 6-16 weeks of age are injected subcutaneously with 1×105TC-1 cells (ATCC, VA) in the right or left rear flank. Beginning about 2weeks after cell injection, tumors are measured with calipers every 2-4d until the tumor size required the mice are killed. At the time ofsacrifice animals are subjected to a full necropsy and spleens andtumors removed. Excised tumors are measured and weighed. Compounds maybe administered before and/or after tumor injections, and a delay orinhibition of tumor growth used to assess compound efficacy.

Intermediates 1 to 4 are potent C5aR antagonists with IC₅₀≤5 nM in thechemotaxis assay using U937 cells as described in Example 65.Characterization data for Examples 1-64 are provided in Table 1 (below).

TABLE 1 Structure, Characterization Data of Specific Embodiments MS:(ES) m/z Example No. Structure [M + H]⁺ R_(t) (min)  1

783.2 2.37 (Method A)  2

748.2 2.67 (method A)  3

645.4 3.45 (Method A)  4

719.2 2.50 (Method A)  5

737.2 3.07 (Method A)  6

724.2 2.95 (Method A)  7

746.2 3.60 (Method A)  8

847.2 3.11 (Method A)  9

914.1 2.68 (Method A) 10

840.0 2.73 (Method A) 11

813.2 2.76 (Method A) 12

853.0 2.85 (Method A) 13

964.0 2.89 (Method A) 14

941.0 2.68 (Method A) 15

797.1 2.92 (Method A) 16

784.2 3.18 (Method A) 17

893.1 2.83 (Method A) 18

877.1 2.77 (Method A) 19

859.2 2.86 (Method A) 21

841.2 3.86 (Method B) 21

843.2 2.95 (Method A) 22

917.1 3.67 (Method B) 23

905.3 4.71 (Method C) 24

853.0 3.51 (Method B) 25

696.2 3.67 (Method B) 26

738.2 3.34 (Method B) 27

760.1 3.54 (Method B) 28

802.2 3.55 (Method B) 29

864.2 3.84 (Method B) 30

788.2 4.96 (Method C) 31

811.2 5.36 (Method A) 32

595.5 4.88 (Method C) 33

622.2 2.51 (Method A) 34

664.2 2.68 (Method A) 35

679.2 2.27 (Method A) 36

693.3 2.09 (Method A) 37

650.3 2.60 (Method A) 38

701.9 2.10 (Method A) 39

680.1 2.55 (Method A) 40

721.2 2.62 (Method A) 41

678.3 2.64 (Method A) 42

636.2 2.50 (Method A) 43

712.2 2.80 (Method A) 44

694.2 2.43 (Method A) 45

736.2 2.87 (Method A) 46

694.2 2.45 (Method A) 47

721.2 2.56 (Method A) 48

707.2 2.50 (Method A) 49

677.7 3.25 (Method A) 50

645.6 2.60 (Method A) 51

675.7 2.39 (Method A) 52

741.2 2.95 (Method A) 53

785.1 3.83 (Method A) 54

677.2 2.40 (Method A) 55

721.2 2.35 (Method A) 56

859.2 4.05 (Method A) 57

795.2 2.82 (Method A) 58

913.3 3.06 (Method A) 59

849.2 3.16 (Method A) 60

896.2 2.56 (Method A) 61

986.3 2.93 (Method A) 62

751.2 3.05 (Method A) 63

749.2 4.65 (Method A) 64

696.3 4.69 (Method A)Reverse Phase HPLC Conditions Used for Determination of Retention Timesin Table 1:

Column: ZORBAX (SB-C18 2.1×50 mm, 5 μm)

Mobile phase A: 95% H₂O, 5% MeCN (with 0.1% Formic Acid)

Mobile phase B: 5% H₂O, 95% MeCN (with 0.1% Formic Acid)

Flow rate: 1.0 mL/min

Gradient: 20 to 100% B in 5.5 min (Method A)

-   -   0 to 100% B in 4.5 min (Method B)    -   0 to 100% B in 5.5 min (Method C)

Intravenous Injections in Rats

Male rats, weighing between 0.22 to 0.25 Kg, were purchased from CharlesRiver Laboratories (Hollister, Calif.) and were acclimated before use.All compounds were prepared in solution formulations and administered toanimals through intravenous dosing. Compounds of example 1 and example 4were prepared in 31.6% DMA/36.8% EtOH/31.6% PG and each animal received1 mL/Kg. Blood (0.2 mL) were sampled through the jugular vein or cardiacpunctures (for terminal points only) at pre-dose, 2, 5, 10, 15, and 30min, 1, 2, 4, 6, and 8 hours post-dose for i.v. dosing. Blood sampleswere collected into chilled polypropylene tubes containing potassiumEDTA as anticoagulant and plasma was collected through centrifugation(Eppendorf Centrifuge 5417R) at 10,000 rpm and 4° C. for 6 minutes andstored at −20° C. until analysis.

Plasma samples (50 μL) were extracted with 200 μL acetonitrilecontaining internal standard on a linear shaker for 10 min and thencentrifuged at 4450 rpm for 10 min at 4° C. (Allegra X-15R centrifuge,Beckman Coulter, Inc., Fullerton, Calif.). One hundred μL of theresulting supernatant was transferred into a new plate and mixed with100 μL 0.1% formic acid in water for LC-MS/MS analysis. Good amount ofactive drugs were released after intravenous injection for bothcompounds in male rats as illustrated by FIGS. 1 and 2 .

While particular embodiments of this invention are described herein,upon reading the description, variations of the disclosed embodimentsmay become apparent to individuals working in the art, and it isexpected that those skilled artisans may employ such variations asappropriate. Accordingly, it is intended that the invention be practicedotherwise than as specifically described herein, and that the inventionincludes all modifications and equivalents of the subject matter recitedin the claims appended hereto as permitted by applicable law. Moreover,any combination of the above-described elements in all possiblevariations thereof is encompassed by the invention unless otherwiseindicated herein or otherwise clearly contradicted by context.

All publications, patent applications, accession numbers, and otherreferences cited in this specification are herein incorporated byreference as if each individual publication or patent application werespecifically and individually indicated to be incorporated by reference.

What is claimed is:
 1. A compound of any one of Formulae (IA), (IB), (IC), (IIA), (IIB) or (IIC):

or a pharmaceutically acceptable salt thereof, wherein, ring vertex a is N or C(R^(2c)), ring vertex b is N or C(R^(2d)), and ring vertex a is N or C(R^(2e)), wherein no more than one of a, b and e is N; X¹ is selected from the group consisting of a bond, C₁₋₈ alkylene, C(O), C(O)—C₁₋₄ alkylene, and S(O)₂; R¹ is selected from the group consisting of a) 5- to 10-membered heteroaryl having from 1 to 4 heteroatoms as ring vertices selected from N, O and S; b) C₆₋₁₀ aryl; c) C₃₋₈ cycloalkyl; d) 4- to 8-membered heterocycloalkyl having from 1 to 2 heteroatoms as ring vertices selected from N, O and S; and e) C₁₋₈ alkyl, C₁₋₈ alkoxy, C₁₋₈ haloalkyl, —C(O)NR^(1a)R^(1b), and —CO₂R^(1a); wherein R^(1a) and R^(1b) are each independently selected from the group consisting of hydrogen, C₁₋₈ alkyl, C₆₋₁₀ aryl, and —C₁₋₆ alkylene—C₆₋₁₀ aryl; wherein the group —X¹—R¹ is unsubstituted or substituted with 1 to 5 R^(x) substituents; R^(2a) and ^(2e) are each independently selected from the group consisting of hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, —O—C₁₋₆ haloalkyl, —S—C₁₋₆ alkyl, —C₁₋₆ alkyl—O—C₁₋₆ alkyl, —C₁₋₆ alkyl—S—C₁₋₆ alkyl, CN, and halogen, and at least one of R^(2a) and ^(2e) is other than hydrogen; R^(2b), R^(2c), and R^(2d) are each independently selected from the group consisting of hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, —O—C₁₋₆ haloalkyl, —S—C₁₋₆ alkyl, —C₁₋₆ alkyl—O—C₁₋₆ alkyl, —C₁₋₆ alkyl—S—C₁₋₆ alkyl, cyano, and halogen; each R³ is independently selected from the group consisting of hydroxyl, C₁₋₄ alkyl, C₁₋₄ haloalkyl and C₁₋₄ hydroxyalkyl, and optionally two R³ groups on the same carbon atom are combined to form oxo (═O), and optionally two R³ groups and the carbon atoms they are attached to form a 3-6 membered ring with 0-2 hetereoatoms as ring members selected from O, N, and S; R⁴ is a member selected from the group consisting of: —NHP¹, —NHC(O)NHP¹, —CH₂NHP¹ and —CH₂NHC(O)NHP¹; each R⁵ is independently selected from the group consisting of C₁₋₈ alkyl, C₁₋₈ alkoxy, C₁₋₈ haloalkyl, C₁₋₈ haloalkoxy, C₁₋₈ hydroxyalkyl, halogen, OH, CN, C(O)R^(5a) and CO₂R^(5a); R^(5′) is a member selected from the group consisting of hydrogen, C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₁₋₈ hydroxyalkyl, C(O)R^(5a) and CO₂R^(5a); wherein each R^(5a) is independently selected from the group consisting of hydrogen, C₁₋₄ alkyl, and C₁₋₄ haloalkyl; R⁶ is a member selected from the group consisting of hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, —O—C₁₋₆ haloalkyl, —S—C₁₋₆ alkyl, —C₁₋₆ alkyl—O—C₁₋₆ alkyl, —C₁₋₆ alkyl—S—C₁₋₆ alkyl, cyano, and halogen; R⁷ is P¹; and R⁸ is —CH₂OP¹; each P¹ is (i) selected from the group consisting of:

wherein each R⁹ is independently selected from the group consisting of H and C₁₋₃ alkyl; and each R¹⁰ is independently selected from the group consisting of H, C₁₋₃ alkyl, phenyl, and benzyl; (ii) selected from the group consisting of:

wherein each R^(y) is independently selected from the group consisting of —OP(O)(OR^(y1))₂, —OC(O)CH₂N(R^(y2))₂, —N(R^(y2))₂, and piperazine; each R^(y1) is independently selected form the group consisting of H, C₁₋₃ alkyl, and benzyl; each R^(y2) is independently H or C₁₋₃ alkyl; and each phenyl ring bearing an R^(y) or —CH₂R^(y) substituent is further substituted with from 0 to 3 members independently selected from the group consisting of nitro, halogen, CN, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, and C₁₋₄ hydroxyalkyl; (iii) selected from the group consisting of —CH₂OH,—P(O)(OR¹⁰)₂, and —CH₂—O—P(O)(OR¹⁰)₂, wherein each R¹⁰ is independently selected from the group consisting of H, C₁₋₃ alkyl, phenyl, and benzyl; (iv) selected from the group consisting of an amino acid, a dipeptide, and a tripeptide; or (v) selected from the group consisting of:

each R^(x) is independently selected from the group consisting of halogen, CN, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₁₋₄ hydroxyalkyl, C₂₋₄ alkenyl, C₃₋₆ cycloalkyl, CO₂—C₁₋₄ alkyl, and CONH₂; the subscript m is 0, 1, 2, 3 or 4; and the subscript n is 0, 1, 2 or
 3. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein P¹ is selected from the group consisting of:

wherein each R⁹ is independently selected from the group consisting of H and C₁₋₃ alkyl; and each R¹⁰ is independently selected from the group consisting of H, C₁₋₃ alkyl, phenyl, and benzyl.
 3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein P¹ is selected from the group consisting of:

wherein each R^(y) is independently selected from the group consisting of —OP(O)(OR^(y1))₂, —OC(O)CH₂N(R^(y2))₂, —N(R^(y2))₂, and piperazine; each R^(y1) is independently selected form the group consisting of H, C₁₋₃ alkyl, and benzyl; each R^(y2) is independently H or C₁₋₃ alkyl; and each phenyl ring bearing an R^(y) or —CH₂R^(y) substituent is further substituted with from 0 to 3 members independently selected from the group consisting of nitro, halogen, CN, CF₃, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, and C₁₋₄ hydroxyalkyl.
 4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein P¹ is selected from the group consisting of —CH₂OH, — P(O)(OR¹⁰), and —CH₂—O—P(O)(0R¹⁰)₂, wherein each R¹⁰ is independently selected from the group consisting of H, C₁₋₃ alkyl, phenyl, and benzyl.
 5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein P¹ is selected from the group consisting of an amino acid, a dipeptide, and a tripeptide.
 6. The compound of claim 1, where said amino acid, dipeptide, or tripeptide moieties are independently selected from the group consisting of glycine, alanine, valine, leucine, isoleucine, lysine, cysteine, aspartate, glutamate, histidine, and phenylalanine, wherein the N atom of each amino acid unit may be methylated or acylated.
 7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein P¹ is selected from the group consisting of:


8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X¹ is C(O)—C₁₋₄ alkylene or S(O)₂.
 9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R¹ is a 5- to 10-membered heteroaryl having from 1 to 4 heteroatoms as ring vertices selected from N, O and S; and wherein the group —X¹—R¹ is optionally substituted with 1 to 4 R^(x) substituents.
 10. The compound of claim 9, wherein R¹ is selected from the group consisting of pyrazolyl, pyridyl, pyrimidinyl, imidazolyl, thiazolyl, thiadiazolyl and pyrazinyl; and wherein the group —X¹—R¹ is optionally substituted with 1 to 4 R^(x) substituents.
 11. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R¹ is C₆₋₁₀ aryl; and wherein the group —X¹—R¹ is optionally substituted with 1 to 4 R^(x) substituents.
 12. The compound of claim 11, wherein R¹ is phenyl; and wherein the group —X¹—R¹ is optionally substituted with 1 to 4 R^(x) substituents.
 13. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R¹ is C₃₋₈ cycloalkyl; and wherein the group —X¹—R¹ is optionally substituted with 1 to 4 R^(x) substituents.
 14. The compound of claim 13, wherein R¹ is selected from the group consisting of cyclobutyl, cyclopentyl and cyclohexyl; and wherein the group —X¹—R¹ is optionally substituted with 1 to 4 R^(x) substituents.
 15. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R¹ is a 4- to 8-membered heterocycloalkyl having from 1 to 2 heteroatoms as ring vertices selected from N, O and S; and wherein the group —X¹—R¹ is optionally substituted with 1 to 4 R^(x) substituents.
 16. The compound of claim 15, wherein R¹ is selected from the group consisting of oxetanyl, tetrahydrofuranyl, tetrahydropyranyl and morpholinyl; and wherein the group —X¹—R¹ is optionally substituted with 1 to 4 R^(x) substituents.
 17. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R¹ is selected from the group consisting of C₁₋₈ alkyl, C₁₋₈ alkoxy, C₁₋₈ haloalkyl, —C(O)NR^(1a)R^(1b), and —CO₂R^(1a); wherein R^(1a) and R^(1b) are each independently selected from the group consisting of hydrogen, C₁₋₈ alkyl, C₆₋₁₀ aryl, and —C₁₋₆ alkylene—C₆₋₁₀ aryl; and wherein the group —X¹—R¹ is optionally substituted with 1 to 4 R^(x) substituents.
 18. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R¹ is selected from the group consisting of phenyl, pyridyl, pyrimidinyl, and pyrazinyl; and wherein the group —X¹—R¹ is optionally substituted with 1 to 4 R^(x) substituents.
 19. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ring vertices a and b are CH; R^(2b) is H; ring vertex e is C(R^(2e)), and R^(2a) and R^(2e) are independently selected from the group consisting of C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl,—O—C₁₋₆ haloalkyl, —S—C₁₋₆ alkyl, —C₁₋₆ alkyl—O—C₁₋₆ alkyl, —C₁₋₆ alkyl—S—C₁₋₆ alkyl, CN, and halogen.
 20. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein ring vertices a and b are CH; R^(2b) is H; ring vertex e is C(R^(2e)), and R^(2a) and R^(2e) are independently selected from the group consisting of C₁₋₆ alkyl, C₁₋₆ alkoxy and halogen.
 21. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1 or 2 and each R⁵, when present, is selected from the group consisting of F, Cl, CN, C₁₋₄ alkyl and C₁₋₄ alkoxy.
 22. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1 or 2 and each R⁵, when present, is selected from the group consisting of F, Cl, CN, CH₃ and OCH₃.
 23. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein m is 0, 1 or 2 and each R³, when present, is C₁₋₄ alkyl.
 24. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R¹ is selected from the group consisting of phenyl or pyridyl, wherein the group —X¹—R¹ is optionally substituted with 1 to 4 R^(x) substituents; ring vertices a and b are CH; R^(2b) is H; ring vertex e is C(R^(2e)), and R^(2a) and R^(2e) are independently selected from the group consisting of C₁₋₆ alkyl, C₁₋₆ alkoxy and halogen; m is 0, 1 or 2 and each R³, when present, is CH₃, n is 0, 1 or 2 and each R⁵, when present, is selected from the group consisting of F, Cl, CN, CH₃ and OCH₃.
 25. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R¹ is selected from the group consisting of


26. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein —X¹—R¹ is selected from the group consisting of:


27. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R¹ is selected from the group consisting of:


28. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R¹ is selected from the group consisting of:


29. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R¹ is selected from the group consisting of:


30. The compound of claim 1, or a pharmaceutically

acceptable salt thereof, wherein is selected from the group consisting of


31. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein n is
 0. 32. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 2 and the two R³ groups are on the same carbon atom and are combined to form oxo (═O).
 33. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
 34. The pharmaceutical composition of claim 33, formulated for oral, intravenous, transdermal or subcutaneous administration.
 35. The pharmaceutical composition of claim 33, further comprising one or more additional therapeutic agents.
 36. The pharmaceutical composition of claim 35, wherein the one or more additional therapeutic agent is selected from the group consisting of corticosteroids, steroids, immunosuppressants, Immunoglobulin G agonists, Dipeptidyl peptidase IV inhibitors, Lymphocyte function antigen-3 receptor antagonists, Interleukin-2 ligands, Interleukin-1 beta ligand inhibitors, IL-2 receptor alpha subunit inhibitors, HGF gene stimulators, IL-6 antagonists, IL-5 antagonists, Alpha 1 antitrypsin stimulators, Cannabinoid receptor antagonists, Histone deacetylase inhibitors, AKT protein kinase inhibitors, CD20 inhibitors, Abl tyrosine kinase inhibitors, JAK tyrosine kinase inhibitors, TNF alpha ligand inhibitors, Hemoglobin modulators, TNF antagonists, proteasome inhibitors, CD3 modulators, Hsp 70 family inhibitors, Immunoglobulin agonists, CD30 antagonists, tubulin antagonists, Sphingosine-1-phosphate receptor-1 agonists, connective tissue growth factor ligand inhibitors, caspase inhibitors, adrenocorticotrophic hormone ligands, Btk tyrosine kinase inhibitors, Complement C1s subcomponent inhibitors, Erythropoietin receptor agonists, B-lymphocyte stimulator ligand inhibitors, Cyclin-dependent kinase-2 inhibitors, P-selectin glycoprotein ligand-1 stimulators, mTOR inhibitors, Elongation factor 2 inhibitors, Cell adhesion molecule inhibitors, Factor XIII agonists, Calcineurin inhibitors, Immunoglobulin G1 agonists, Inosine monophosphate dehydrogenase inhibitors, Complement C1s subcomponent inhibitors, Thymidine kinase modulators, Cytotoxic T-lymphocyte protein-4 modulators, Angiotensin II receptor antagonists, Angiotensin II receptor modulators, TNF superfamily receptor 12A antagonists, CD52 antagonists, Adenosine deaminase inhibitors, T-cell differentiation antigen CD6 inhibitors, FGF-7 ligands, dihydroorotate dehydrogenase inhibitors, Syk tyrosine kinase inhibitors, Interferon type I receptor antagonists, Interferon alpha ligand inhibitors, Macrophage migration inhibitory factor inhibitors, Integrin alpha-V/beta-6 antagonists, Cysteine protease stimulators, p38 MAP kinase inhibitors, TP53 gene inhibitors, Shiga like toxin I inhibitors, Fucosyltransferase 6 stimulators, Interleukin 22 ligands, IRS1 gene inhibitors, Protein kinase C stimulators, Protein kinase C alpha inhibitors, CD74 antagonists, Immunoglobulin gamma Fc receptor IIB antagonists, T-cell antigen CD7 inhibitors, CD95 antagonists, N acetylmannosamine kinase stimulators, Cardiotrophin-1 ligands, Leukocyte elastase inhibitors, CD40 ligand receptor antagonists, CD40 ligand modulators, IL-17 antagonists, TLR-2 antagonists, Mannan-binding lectin serine protease-2 (MASP-2) inhibitors, Factor B inhibitors, Factor D inhibitors, C3aR modulators, C5aR2 modulators, T cell receptor antagonists, PD-1 inhibitors, PD-L1 inhibitors, TIGIT inhibitors, TIM-3 inhibitors, LAG-3 inhibitors, VISTA inhibitors, STING agonists, IDO inhibitors, adenosine receptor modulators, CD39 inhibitors, CD73 inhibitors, antagonists of the chemokine receptors, especially CXCR1, CXCR2, CXCR3, CXCR4, CXCR7, CCR1, CCR2, CCR3, CCR4, CCR5, CCR7, CCR7, CCR9, CX3CR1 and CXCR6, and combinations thereof.
 37. The pharmaceutical composition of claim 35, wherein the one or more additional therapeutic agent is selected from the group consisting of obinutuzumab, rituximab, ocrelizumab, cyclophosphamide, prednisone, hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, prednisolone, methylprednisolone, triamcinolone acetonide, triamcinolone alcohol, mometasone, amcinonide, budesonide, desonide, fluocinonide, fluocinolone acetonide, halcinonide, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, fluocortolone, hydrocortisone-17-valerate, halometasone, alclometasone dipropionate, beclomethasone, betamethasone valerate, betamethasone dipropionate, prednicarbate, clobetasone-17-butyrate, clobetasol-17-propionate, fluocortolone caproate, fluocortolone pivalate, fluprednidene acetate, hydrocortisone-17-butyrate, hydrocortisone-17-aceponate, hydrocortisone-17-buteprate, ciclesonide and prednicarbate, GB-0998, immuglo, begelomab, alefacept, aldesleukin, gevokizumab, daclizumab, basiliximab, inolimomab, beperminogene perplasmid, sirukumab, tocilizumab, clazakizumab, mepolizumab, fingolimod, panobinostat, triciribine, nilotinib, imatinib, tofacitinib, momelotinib, peficitinib, itacitinib, infliximab, PEG-bHb-CO, etanercept, ixazomib, bortezomib, muromonab, otelixizumab, gusperimus, brentuximab vedotin, Ponesimod, KRP-203, FG-3019, emricasan, corticotropin, ibrutinib, cinryze, conestat, methoxy polyethylene glycol-epoetin beta, belimumab, blisibimod, atacicept, seliciclib, neihulizumab, everolimus, sirolimus, denileukin diftitox, LMB-2, natalizumab, catridecacog, ciclosporin, tacrolimus, voclosporin, voclosporin, canakinumab, mycophenolate, mizoribine, CE-1145, TK-DLI, abatacept, belatacept, olmesartan medoxomil, sparsentan, TXA-127, BIM-023, alemtuzumab, pentostatin, itolizumab, palifermin, leflunomide, PRO-140, cenicriviroc, fostamatinib, anifrolumab, sifalimumab, BAX-069, BG-00011, losmapimod, QPI-1002, ShigamAbs, TZ-101, F-652, reparixin, ladarixin, PTX-9908, aganirsen, APH-703, sotrastaurin, sotrastaurin, milatuzumab, SM-101, T-Guard, APG-101, DEX-M74, cardiotrophin-1, tiprelestat, ASKP-1240, BMS-986004, HPH-116, KD-025, OPN-305, TOL-101, defibrotide, pomalidomide, Thymoglobulin, laquinimod, remestemcel-L, Equine antithymocyte immunoglobulin, Stempeucel, LIV-Gamma, Octagam 10%, t2c-001, 99mTc-sestamibi, Clairyg, Prosorba, pomalidomide, laquinimod, teplizumab, FCRx, solnatide, foralumab, ATIR-101, BPX-501, ACP-01, ALLO-ASC-DFU, irbesartan+propagermanium, ApoCell, cannabidiol, RGI-2001, saratin, anti-CD3 bivalent antibody-diphtheria toxin conjugate, NOX-100, LT-1951, OMS721, ALN-CCS, ACH-4471, AMY-101, Acthar gel, and CD4+CD25+ regulatory T-cells, MEDI7814, P32, P59, pembrolizumab, nivolumab, atezolizumab, avelumab, durvalumab, CCX354, CCX721, CCX9588, CCX140, CCX872, CCX598, CCX6239, CCX587, CCX624, CCX282, CCX025, CCX507, CCX430, CCX765, CCX758, CCX771, CCX662, CCX650, and combinations thereof.
 38. A method of treating a human suffering from or susceptible to a disease or disorder involving pathologic activation of C5a receptors, comprising administering to the mammal a therapeutically effective amount of a compound of claim
 1. 39. The method of claim 38, wherein the disease or disorder is selected from the group consisting of neutropenia, neutrophilia, Wegener's granulomatosis, microscopic polyangiitis, C3-glomerulopathy, C3-glomerulonephritis, dense deposit disease, membranoproliferative glomerulonephritis, Kawasaki disease, sepsis, septic shock, Hemolytic uremic syndrome, atypical hemolytic uremic syndrome (aHUS), Alzheimer's disease, multiple sclerosis, stroke, inflammatory bowel disease, chronic obstructive pulmonary disorder, inflammation associated with burns, lung injury, osteoarthritis, atopic dermatitis, chronic urticaria, ischemia-reperfusion injury, acute respiratory distress syndrome, systemic inflammatory response syndrome, multiple organ dysfunction syndrome, Uveitis, tissue graft rejection, hyperacute rejection of transplanted organs, myocardial infarction, coronary thrombosis, vascular occlusion, post-surgical vascular reocclusion, artherosclerosis, polypoidal choroidal vasculopathy, traumatic central nervous system injury, ischemic heart disease, rheumatoid arthritis, systemic lupus erythematosus, Guillain-Barre syndrome, pancreatitis, lupus nephritis, lupus glomerulonephritis, psoriasis, Crohn's disease, vasculitis, ANCA vasculitis, irritable bowel syndrome, dermatomyositis, multiple sclerosis, bronchial asthma, pemphigus, pemphigoid, scleroderma, myasthenia gravis, autoimmune hemolytic and thrombocytopenic states, Goodpasture's syndrome, immuno vasculitis, Graft versus host disease, Paroxysmal nocturnal hemoglobinuria, Sjoegrens syndrome, insulin-dependent diabetes, mellitus, lupus nephropathy, Heyman nephritis, membranous nephritis, glomerulonephritis, IGA nephropathy, Membranoproliferative glomerulonephritis, Antiphospholipid syndrome, Age related macular degeneration; Dry age related macular degeneration, Wet age related macular degeneration, Motor neurone disease, contact sensitivity responses, hidradenitis suppurativa, and inflammation resulting from contact of blood with artificial surfaces.
 40. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having the structure selected from


41. The compound of claim 40, or a pharmaceutically acceptable salt thereof, having the structure


42. The compound of claim 40, or a pharmaceutically acceptable salt thereof, having the structure


43. The compound of claim 40, or a pharmaceutically acceptable salt thereof, having the structure 